The term amyloidosis refers to a fascinating group of disorders that share a common pathogenesis of extracellular deposition of amyloid material. Fundamentally, it is a disorder of the secondary structure of select proteins whereby the amyloidogenic proteins are misfolded into a β-pleated sheet configuration, resulting in the formation of insoluble extracellular amyloid fibrils. The amyloid fibrils appear as amorphous eosinophilic material when hematoxylin and eosin–stained tissue is examined under light microscope. Electron microscopy reveals remarkable similarity between the amyloid fibrils derived from different precursor proteins in that they range from 7.5 to 10 nm in diameter. This ultrastructural similarity is the underlying basis for the characteristic red-green birefringence with Congo red staining observed under polarized microscopy, the pathological hallmark of the disease.

To read the full article in PDF:

Click here

The term amyloidosis refers to a fascinating group of disorders that share a common pathogenesis of extracellular deposition of amyloid material. Fundamentally, it is a disorder of the secondary structure of select proteins whereby the amyloidogenic proteins are misfolded into a β-pleated sheet configuration, resulting in the formation of insoluble extracellular amyloid fibrils. The amyloid fibrils appear as amorphous eosinophilic material when hematoxylin and eosin–stained tissue is examined under light microscope. Electron microscopy reveals remarkable similarity between the amyloid fibrils derived from different precursor proteins in that they range from 7.5 to 10 nm in diameter. This ultrastructural similarity is the underlying basis for the characteristic red-green birefringence with Congo red staining observed under polarized microscopy, the pathological hallmark of the disease.

To read the full article in PDF:

Click here

The term amyloidosis refers to a fascinating group of disorders that share a common pathogenesis of extracellular deposition of amyloid material. Fundamentally, it is a disorder of the secondary structure of select proteins whereby the amyloidogenic proteins are misfolded into a β-pleated sheet configuration, resulting in the formation of insoluble extracellular amyloid fibrils. The amyloid fibrils appear as amorphous eosinophilic material when hematoxylin and eosin–stained tissue is examined under light microscope. Electron microscopy reveals remarkable similarity between the amyloid fibrils derived from different precursor proteins in that they range from 7.5 to 10 nm in diameter. This ultrastructural similarity is the underlying basis for the characteristic red-green birefringence with Congo red staining observed under polarized microscopy, the pathological hallmark of the disease.

To read the full article in PDF:

Click here

Each year in the United States, more than 8 million people come to the emergency department with chest pain, but only a minority are eventually diagnosed with a heart attack.¹

Confronted with signs and symptoms that could represent an acute coronary syndrome, clinicians need to know whether the patient has a benign condition and can safely be sent home or is in urgent need of hospitalization—and they need to do so in a safe, timely, and cost-effective manner.^2,3

Testing for biomarkers of cardiac injury, especially troponins I and T, is an accepted part of the assessment of chest pain. However, the interpretation of these cardiac biomarkers is complicated by the fact they can be elevated from noncoronary causes of chest pain such as pulmonary embolism or renal impairment, and thus should be considered only as part of the patient’s total clinical picture. This uncertainty can result in longer hospital stays and increased testing.

Thus, researchers are searching for new biomarkers that could allow for more rapid and accurate diagnosis and estimation of prognosis.

In this article we will examine the advantages and limitations of measuring cardiac biomarkers. We then discuss the emerging data on new biomarkers, including the very promising high-sensitivity troponin assays, cystatin C, and other markers, and the potential for biomarkers to be used instead of or in combination with stress testing in the evaluation of patients who have no initial evidence of ischemia.

SCENARIO 1: ELEVATED TROPONIN AND ST-SEGMENT ELEVATION

A 46-year-old woman presents to the emergency department with chest pain that started 2 hours earlier. Electrocardiography (ECG) initially shows sinus tachycardia with ST-segment depression and negative T waves in lead aVL. Her cardiac biomarker values (troponin I and creatine kinase MB) are normal. Repeated troponin I measurements show elevations of 250 ng/L, whereas her creatine kinase MB level is within the optimal range. Coronary angiography is unremarkable. Echocardiography shows right ventricular pressure overload in the pulmonary artery and the right ventricle. How should this patient be further evaluated?

SCENARIO 2: ELEVATED TROPONIN AND LEFT VENTRICULAR HYPERTROPHY

A 47-year-old man is admitted with worsening dyspnea and chest pain that worsens with coughing and inspiration. He has a history of end-stage renal disease secondary to poorly controlled hypertension and is being treated with hemodialysis, which he missed for the past 4 weeks while failing to take his hypertension medication. His blood pressure is 270/130 mm Hg. Chest auscultation reveals signs of pulmonary edema—ie, crackles at the end of inspiration. His troponin T level is 394 ng/L. ECG indicates left ventricular hypertrophy. How should this patient be further evaluated?

TROPONIN IS SPECIFIC FOR INJURY, BUT NOT FOR INFARCTION

American College of Cardiology and American Heart Association (ACC/AHA) guidelines⁴ recommend that clinicians ask themselves two questions: what is the likelihood that the patient is truly having an acute coronary syndrome secondary to coronary artery disease, and what is the likelihood of an adverse clinical outcome? Clues come from the initial measurements of biomarkers of cardiac injury, history, physical examination, and ECG (Table 1),⁵ and subsequent care is based on the estimated degree of risk.

Troponin revolutionized the diagnosis and risk stratification of chest pain. The ACC/AHA guidelines call for measuring biomarkers—preferably troponin—in all patients who present with chest discomfort consistent with an acute coronary syndrome.^4,6

Cardiac troponins I and T have been the biomarkers of choice for detecting myocardial injury,^4,6 since elevated concentrations are highly sensitive and tissue-specific.⁷ Moreover, they identify patients at short-term and long-term risk of cardiac events.^4,8

The introduction of troponin testing led to a substantial increase in the rate of diagnosis of myocardial infarction (MI), with an increase in cardiac care unit admissions of more than 20%.^9,10 This was partly because troponin is released into the blood with even minute myocardial damage, so that some patients who previously would have been diagnosed with unstable angina are now found to have non-ST-segment-elevation MI.¹⁰ However, the increase in admissions may also represent an increase in misdiagnoses, with many clinicians equating an elevated troponin level with acute MI.¹¹

Although an elevated troponin level is 100% specific for myocardial injury, it is not synonymous with MI.¹² Myocardial injury can be caused by a cardiac condition such as tachyarrhythmia, cardiac trauma, congestive heart failure, ventricular hypertrophy, myocarditis, or pericarditis, or by a noncardiac condition such as sepsis, respiratory failure, pulmonary embolism, pulmonary hypertension, cancer chemotherapy, or renal insufficiency.^4,13 Therefore, to avoid a misdiagnosis of MI, the troponin level must be considered in the clinical context.

In fact, Alcalai et al¹¹ noted that almost half of patients with elevated troponin did not really have an acute coronary syndrome. More importantly, in-hospital and long-term survival rates were significantly better for patients with an acute coronary syndrome than for those without, illustrating the importance of identifying and treating the true disease instead of mislabeling the problem as MI.

Bayesian theory predicts that patients with chest pain who have elevated troponin are less likely to truly have an acute coronary syndrome if the rest of their clinical presentation indicates a low probability for heart disease.¹⁴ Indeed, when McDonald et al¹⁵ used a risk-scoring index based on sex, a history of heart failure or coronary artery disease, the ECG, and use of aspirin, the positive predictive value of an abnormal troponin level was 83% at a risk score of 4 or greater, 63% at a score of 3, 52% at a score of 2, 32% at a score of 1, and 29% at a score of 0.

Thus, cardiac biomarkers are not a substitute for traditional clinical assessment, but rather should be used “in conjunction with the clinical history, physical examination, and interpretation of the ECG.”⁶ Consequently, diagnostic protocols that incorporate pretest clinical features to identify low-risk patients have a higher negative predictive value.

This was illustrated in a study by Than et al¹⁶ that aimed to prospectively validate the safety of an accelerated diagnostic protocol to assess chest pain suggestive of an acute coronary syndrome. The protocol included a structured pretest probability scoring method (ie, the Thrombolysis in Myocardial Infarction [TIMI] score), ECG, and a point-of-care biomarker panel of troponin, creatine kinase MB, and myoglobin. The protocol had a negative predictive value of 99.1%, whereas the use of biomarkers alone had a value of 96.1%.

HISTORY AND PHYSICAL EXAMINATION PROVIDE KEY INFORMATION

In a review, Heidenreich et al⁸ noted certain demographic characteristics associated with worse outcomes—ie, older age and male sex; a history of medical conditions such as diabetes, MI, and hypertension; and heart failure on presentation.

A careful assessment of chest pain and associated symptoms helps narrow the differential diagnosis. Features that increase the likelihood of a cardiac origin of chest pain are:

• Chest pain at the time of presentation (likelihood ratio [LR] = 2.0)
• Radiation of the pain to the right shoulder (LR = 2.9), the left arm (LR = 2.3), or both arms (LR = 7.1)
• Nausea or vomiting (LR = 1.9)
• Diaphoresis (LR = 2.0).¹⁷

The physical examination can detect highrisk features such as new murmurs, hypotension, diaphoresis, pulmonary edema, and rales. It is more specific than sensitive and is useful in identifying low-risk patients by targeting potential noncardiac causes of the patient’s symptoms.¹⁸

The efficacy of clinical assessment was studied in 2,271 patients with chest pain presenting to the emergency department.¹⁹ In this cohort, a low-risk group with a 30-day major cardiovascular event rate (death, MI, stroke, or revascularization) of 2.5% could be identified through the use of the US Agency for Health Care Policy and Research criteria.

Electrocardiography

ECG provides important diagnostic and prognostic information and independently predicts death or MI, even after adjustment for cardiac biomarker measurements,^20,21 making it pivotal in the evaluation.⁴ The key features on ECG that increase the probability of MI are:

• New ST-segment elevation (LR 5.7–53.9)
• New Q waves (LR 5.3–24.8).¹⁷

One study²⁰ found that while the troponin T level was a powerful independent marker in patients presenting with MI, its value for risk stratification was enhanced when it was combined with a standard measure such as ECG.²⁰ While more than 90% of patients with STsegment elevation had an adverse outcome, only 31.7% of those patients had an elevated troponin T level.

No component is sufficient by itself

Thus, in spite of the proliferation of cardiac diagnostic tests, the initial bedside assessment of chest pain remains paramount. In fact, in patients presenting to the emergency department with chest pain, low risk (ie, those with a < 5% probability of MI) may be identified by presenting symptoms, medical history, and ECG alone.¹⁹

Furthermore, although clinical assessment, ECG, and cardiac biomarker testing each provide incremental benefit in assessing chest pain, no component is sufficient by itself. Sanchis et al²² found that even in patients with a normal troponin I level, the risk remained high in the case of ST-segment depression, and that even without signs of ischemia, the probability of cardiac events was 16% when the chest pain score was 11 points or higher.²² Consequently, a normal troponin level, ECG, or any other predictor alone would not ensure a good prognosis.

BIOMARKERS INSTEAD OF STRESS TESTING?

The ACC/AHA guidelines for the diagnosis of patients with unstable angina and non-STsegment elevation MI say that stable patients at low risk with no evidence of ischemia on initial assessment can be admitted to a chest pain unit for observation with serial cardiac biomarkers and ECG.⁴ At the end of the observation period, those who have reassuring results on ECG and normal cardiac biomarker measurements undergo functional cardiac testing or stress testing, or both.⁴

Exercise treadmill testing is a cornerstone of confirmatory testing in an accelerated diagnostic protocol because it is readily available, safe, and easy to do.¹⁸ A low-risk result was shown to have a high negative predictive value,^23,24 so that the likelihood of an acute coronary syndrome is low enough for safe discharge.

However, the overall process is not ideal since it is time-consuming, generates additional costs, and can have false-positive results in patients who are otherwise deemed not to be at high risk. While some studies provided an optimistic view about discharging low-risk patients with negative biomarkers without stress testing,^7,25 others have discouraged omitting exercise treadmill testing from protocols.^22,26

Others have proposed combining a biomarker with an imaging study such as coronary computed tomographic (CT) angiography.²⁷ Normal findings on this study have been shown to have a negative predictive value of up to 100% for ruling out an acute coronary syndrome and the occurrence of major adverse cardiovascular events in the long term.^28,29 Furthermore, it allows more-inclusive assessments of chest pain and can exclude other life-threatening causes such as pulmonary embolism and aortic dissection (referred to as the “triple rule-out”).³⁰

However, 25% to 50% of patients presenting to the emergency department with chest pain may not be candidates for CT angiography because of obesity, contrast allergy, intolerance to beta-blockade, arrhythmia, renal insufficiency, or a history of coronary artery disease.¹⁸ Moreover, it may be more efficient and less costly to discharge some patients without coronary CT angiography³¹ with the help of novel biomarkers without routine additional testing. This may spare patients the additional radiation exposure from CT angiography or nuclear imaging.^27,32

New biomarkers may, it is hoped, better distinguish patients at low risk from those at high risk without resorting to stress testing. Several of these markers are moving toward mainstream clinical use. For a biomarker to be prognostically equivalent to stress testing, it must be able to tell us if the likelihood of an acute coronary syndrome is low enough for safe discharge—ie, it must have a significantly high negative predictive value. Also, it must be an independent predictor of adverse outcomes, particularly in patients deemed at low risk by initial low troponin measurements. Biomarkers that have shown promise in this regard include high-sensitivity troponin, brain-type natriuretic peptide (BNP), cystatin C, and ischemia-modified albumin.

HIGH-SENSITIVITY CARDIAC TROPONIN ASSAYS

Although we speak of “high-sensitivity troponin,” these new assays detect the same molecule as do traditional troponin assays. The difference is that high-sensitivity assays can detect and measure troponin at concentrations much lower than the traditional assays can. In fact, high-sensitivity troponin assays can detect and measure troponin at very low levels in almost all healthy people.

Studies have shown that the high-sensitivity assays have better analytical accuracy and sensitivity than older assays.¹²

Aldous et al³³ reported that, in patients who presented to the emergency department within 4 hours of the onset of chest pain, an elevation in troponin T on a high-sensitivity assay had a positive predictive value of 53.8% and a negative predictive value of 98.3%.

Weber et al³⁴ found the diagnostic value of the high-sensitivity troponin T assay to be superior to that of a contemporary troponin T assay (area under the receiver-operating-characteristics curve [AUC] of 0.949 vs 0.929). Even when the contemporary troponin T assay was negative, the high-sensitivity assay provided strong diagnostic information (AUC 0.81). Furthermore, the high-sensitivity assay provided superior independent prognostic power for death within 6 months.

Hochholzer et al³⁵ reported a prognostic accuracy for death significantly higher (AUC 0.79) than that of contemporary troponin T (AUC 0.69). A concentration of high-sensitivity troponin T above 14 ng/L improved the prediction of death (hazard ratio 2.60) but not of subsequent acute MI in patients with acute chest pain. Therefore, a negative high-sensitivity troponin T assay identifies patients with a good prognosis and who may be discharged without further testing if their clinical presentation and ECG are also reassuring.

Keller et al³⁶ compared the diagnostic performance of the high-sensitivity cardiac troponin I assay against 11 other biomarkers, including a contemporary cardiac troponin I assay. The contemporary troponin I and the high-sensitivity troponin I assays performed best. The high-sensitivity troponin I assay at admission had a sensitivity of 82.3% and a negative predictive value of 94.7% for ruling out acute MI, whereas the contemporary troponin I assay had a sensitivity of 79.4% and a negative predictive value of 94.0%.

Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both troponin I assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value for ruling in acute MI for high-sensitivity cardiac troponin I increased from 75.1% at admission to 95.8% after 3 hours; for the contemporary assay, it increased from 80.9% at admission to 96.1%.³⁶

The authors concluded that performing either of the cardiac troponin I assays 3 hours after admission may help in ruling out MI early on, with a negative predictive value greater than 99%. Moreover, the relative change in concentration within the 3 hours after admission, combined with the 99th percentile diagnostic cutoff value on admission, improves specificity, allowing acute MI to be accurately ruled in.³⁶

Of note, though studies have confirmed that a measurement at 3 hours identifies most cases of MI early, they have not used the recommended maximal sensitivity interval for troponin measurements (6 hours or more).⁶

A proposed algorithm for diagnosing acute MI with a high-sensitivity assay

While high-sensitivity troponin T assays can improve the early diagnosis of acute MI, how best to use them is yet to be defined. They still lack specificity for acute coronary syndromes, with positive predictive values as low as 50%.³⁷

Reichlin et al³⁸ developed and validated an algorithm for rapidly ruling out or ruling in acute MI using a high-sensitivity cardiac troponin T assay, incorporating baseline values and absolute changes within the first hour. Using a baseline threshold of 12 ng/L or less and an absolute change of 3 ng/L or less, they found a sensitivity and negative predictive value of 100%, making these good criteria for ruling out acute MI.

Using a baseline threshold of 60 ng/L or greater and a change from baseline to 1 hour of at least 15 ng/L, the specificity was 97% and the positive predictive value was 84%, making these good criteria for ruling in acute MI.

Patients whose values were in between were classified as being in an “observationalzone group,” in which the prevalence of acute MI was 8%. The cumulative 30-day survival rate was 99.8% in patients in whom the test ruled out MI, 98.6% in the observational-zone patients, and 95.3% in patients in whom the test ruled in MI.³⁸ Using this simple algorithm allowed a safe rule-out as well as an accurate rule-in of acute MI within 1 hour in 77% of unselected patients with acute chest pain; thus, it may obviate the need for prolonged monitoring and serial measurements in three out of four patients.”

Newby³⁹ stated that such an algorithmic approach must be validated in a prospective study that assesses not only sensitivity, negative predictive value, specificity, and positive predictive value, but also the implications for clinical outcomes and the cost of widespread implementation.

In the meantime, clinicians must keep in mind that patient populations in clinical practice are less selected, the prevalence of MI may broadly vary, and confounding comorbidities such as heart failure and renal insufficiency are more common. Studies are also needed to verify whether other factors such as age, sex, and time from symptom onset should be considered.

BRAIN-TYPE NATRIURETIC PEPTIDE

BNP is a 32-amino-acid natriuretic peptide that is released from myocytes. The amount released depends on wall stress brought on by heart failure, ischemic heart disease, or other conditions.

In a study of the diagnostic utility of BNP in the workup of acute chest pain, Haaf et al⁴⁰ found that BNP levels at presentation were significantly higher in patients with acute MI than in patients with other diagnoses. However, the diagnostic accuracy of BNP was lower than that of cardiac troponin T at presentation, though its independent predictive value for all-cause mortality was more accurate than that of troponin T.

Elevation of the BNP ⁴¹ or the N-terminal pro-BNP ^42,43 level was shown to also provide unique prognostic information in patients with suspected and confirmed acute coronary syndrome and was associated with higher rates of short-term and long-term mortality. Therefore, BNP appears useful for the prognosis but not the diagnosis of acute coronary syndromes.

CYSTATIN C

The protein cystatin C, widely used as a biomarker for kidney disease, has more recently been touted as a prognostic marker in acute coronary syndromes.

Jernberg et al⁴⁴ reported that, in patients with a suspected or confirmed acute coronary syndrome, a single measurement of cystatin C significantly improved the early stratification of risk.⁴⁴ Specifically, the cystatin C level was independently associated with mortality risk but not with the risk of subsequent MI.

In another study,⁴⁵ the cystatin C concentration independently predicted the risk of cardiovascular death or MI in non-ST-segment elevation acute coronary syndrome. However, the additive predictive value of cystatin C in these patients was found to be small when clinical risk factors and biomarkers of MI were used in the prediction model. Therefore, cystatin C may predict global risk but does not appear to be useful in diagnosing MI.

ISCHEMIA-MODIFIED ALBUMIN

A major limitation of troponin is that it cannot detect reversible myocardial ischemia in the absence of cardiac necrosis, making stress testing necessary to unmask potential reversible ischemia.

Ischemia-modified albumin has been proposed as a means of detecting cardiac ischemia even if necrosis is absent. It is a product of the N-terminus alteration of albumin caused by myocardial ischemia, which reduces the ability of cobalt to bind to albumin and can be detected with the albumin cobalt binding test. This marker might have a high negative predictive value, ruling out acute coronary syndromes in conditions of low pretest probability with negative necrosis markers and ECG.^13,46

Although ischemia-modified albumin does show promise, doubt remains as to its validity as a biomarker, as its mechanism of generation is not known. Some have suggested that it is in fact a marker of oxidative stress.⁴⁷

PANELS OF MARKERS

The individual biomarkers we have discussed here have advantages and limitations in the emergency workup of chest pain. The concept of using a multimarker panel has been raised as a way of amplifying the positive attributes of individual biomarkers and compensating for their shortcomings.

Sabatine et al⁴⁸ tested this approach in patients with acute coronary syndromes who were at high risk of an adverse outcome. When patients were categorized at presentation on the basis of the number of elevated biomarkers such as cardiac troponin I, C-reactive protein, and BNP, the risk of death nearly doubled with each additional biomarker that was elevated.

The relationship was similar for the end points of MI, heart failure, and the composite at 30 days and 10 months. In a cohort of 1,635 patients, the number of elevated biomarkers remained a predictor of the composite end point after adjustment for known clinical predictors. The risk of death, MI, or heart failure by 6 months was 2.1 times higher in patients with one elevated biomarker, 3.1 times higher in those with two, and 3.7 times higher in those with three.

The authors concluded that a multimarker strategy that categorizes patients on the basis of the number of elevated biomarkers at presentation allows risk-stratification of short- and long-term cardiac events.

Tello-Montoliu et al⁴⁹ tested this idea in patients with non-ST-segment elevation acute coronary syndromes using a panel consisting of cardiac troponin T, C-reactive protein, N-terminal pro-BNP, and fibrin D-dimer. The risk of a major event (death, new acute coronary syndrome, revascularization, or heart failure) at 6 months was associated with abnormal biomarker levels, especially with the presence of three positive biomarkers, even after adjustment for clinical characteristics and ECG findings.

van der Zee et al⁴³ showed that a positive biomarker panel consisting of C-reactive protein and N-terminal pro-BNP identified patients with chest pain and a normal or nondiagnostic ECG who have a high long-term risk of cardiovascular death.

Glaser et al⁵⁰ evaluated the combination of cardiac troponin I, BNP, homocysteine, C-reactive protein, placental growth factor, myeloperoxidase, choline, soluble CD40 ligand, ischemia-modified albumin, and lipoprotein-associated phospholipase A2 in patients with a suspected acute coronary syndrome. The combination of BNP, placental growth factor, and estimated glomerular filtration rate was the most accurate predictor of major adverse cardiovascular events compared with any other biomarker or clinical factor. With appropriate cutoff values, the negative predictive value for a major adverse cardiovascular event at 1 year was as high as 99.1%.

This study highlighted the importance of combining biomarkers, showing that with a negative predictive value of 97% for 30-day events, the combination of placental growth factor, BNP, and cardiac troponin I may help surmount the delay from symptom onset to cardiac troponin increase, thus permitting a more timely diagnosis and safe discharge within 12 hours.

Comment. These studies raise the promise that panels of biomarkers can be used in patients deemed to be at low risk after clinical assessment and troponin evaluation to enable them to be safely discharged early and to obviate the need for stress testing.

If we assume that unstable cardiac disease requiring hospitalization accounts for 35% of patients with chest pain, a hypothetical panel of biomarkers with a sensitivity and specificity of 95% for adverse cardiac outcomes would have a positive predictive value of 91% and a negative predictive value of 97%. The negative likelihood ratio of this hypothetical biomarker panel would be 0.05, while the positive likelihood ratio would be 19. This performance level means that in patients with a pretest probability less than 50%, the posttest probability can be reduced to below 10%, so that such patients can be safely discharged without further hospital evaluation.

Conversely, a positive test result in patients with pretest probability of 30% or greater raises the posttest probability to nearly 90%, meaning that such patients should be considered for aggressive intervention without the need for stress testing.

RETURN TO OUR SCENARIOS

Chest pain remains a nonspecific complaint, and the interpretation of biomarkers to find the cause presents clinicians with challenges, as illustrated by the cases introduced at the beginning of this article.

The cardiac troponin I elevation in scenario 1 led to an initial diagnosis of unstable angina. However, coronary angiography showed lesion-free coronary arteries, thus excluding ischemic heart disease. When other diseases that could cause elevated cardiac troponin I were considered and investigated with further diagnostic tests such as D-dimer, pulmonary embolism became the new working diagnosis, and this was confirmed by CT angiography.

Similarly, given the laboratory values for the patient in scenario 2, the condition could have been mistaken for an acute coronary syndrome. However, the absence of evidence on ECG to support this diagnosis would indicate an erroneously elevated biomarker secondary to his background of chronic renal insufficiency.

Each year in the United States, more than 8 million people come to the emergency department with chest pain, but only a minority are eventually diagnosed with a heart attack.¹

Confronted with signs and symptoms that could represent an acute coronary syndrome, clinicians need to know whether the patient has a benign condition and can safely be sent home or is in urgent need of hospitalization—and they need to do so in a safe, timely, and cost-effective manner.^2,3

Testing for biomarkers of cardiac injury, especially troponins I and T, is an accepted part of the assessment of chest pain. However, the interpretation of these cardiac biomarkers is complicated by the fact they can be elevated from noncoronary causes of chest pain such as pulmonary embolism or renal impairment, and thus should be considered only as part of the patient’s total clinical picture. This uncertainty can result in longer hospital stays and increased testing.

Thus, researchers are searching for new biomarkers that could allow for more rapid and accurate diagnosis and estimation of prognosis.

In this article we will examine the advantages and limitations of measuring cardiac biomarkers. We then discuss the emerging data on new biomarkers, including the very promising high-sensitivity troponin assays, cystatin C, and other markers, and the potential for biomarkers to be used instead of or in combination with stress testing in the evaluation of patients who have no initial evidence of ischemia.

SCENARIO 1: ELEVATED TROPONIN AND ST-SEGMENT ELEVATION

A 46-year-old woman presents to the emergency department with chest pain that started 2 hours earlier. Electrocardiography (ECG) initially shows sinus tachycardia with ST-segment depression and negative T waves in lead aVL. Her cardiac biomarker values (troponin I and creatine kinase MB) are normal. Repeated troponin I measurements show elevations of 250 ng/L, whereas her creatine kinase MB level is within the optimal range. Coronary angiography is unremarkable. Echocardiography shows right ventricular pressure overload in the pulmonary artery and the right ventricle. How should this patient be further evaluated?

SCENARIO 2: ELEVATED TROPONIN AND LEFT VENTRICULAR HYPERTROPHY

A 47-year-old man is admitted with worsening dyspnea and chest pain that worsens with coughing and inspiration. He has a history of end-stage renal disease secondary to poorly controlled hypertension and is being treated with hemodialysis, which he missed for the past 4 weeks while failing to take his hypertension medication. His blood pressure is 270/130 mm Hg. Chest auscultation reveals signs of pulmonary edema—ie, crackles at the end of inspiration. His troponin T level is 394 ng/L. ECG indicates left ventricular hypertrophy. How should this patient be further evaluated?

TROPONIN IS SPECIFIC FOR INJURY, BUT NOT FOR INFARCTION

American College of Cardiology and American Heart Association (ACC/AHA) guidelines⁴ recommend that clinicians ask themselves two questions: what is the likelihood that the patient is truly having an acute coronary syndrome secondary to coronary artery disease, and what is the likelihood of an adverse clinical outcome? Clues come from the initial measurements of biomarkers of cardiac injury, history, physical examination, and ECG (Table 1),⁵ and subsequent care is based on the estimated degree of risk.

Troponin revolutionized the diagnosis and risk stratification of chest pain. The ACC/AHA guidelines call for measuring biomarkers—preferably troponin—in all patients who present with chest discomfort consistent with an acute coronary syndrome.^4,6

Cardiac troponins I and T have been the biomarkers of choice for detecting myocardial injury,^4,6 since elevated concentrations are highly sensitive and tissue-specific.⁷ Moreover, they identify patients at short-term and long-term risk of cardiac events.^4,8

The introduction of troponin testing led to a substantial increase in the rate of diagnosis of myocardial infarction (MI), with an increase in cardiac care unit admissions of more than 20%.^9,10 This was partly because troponin is released into the blood with even minute myocardial damage, so that some patients who previously would have been diagnosed with unstable angina are now found to have non-ST-segment-elevation MI.¹⁰ However, the increase in admissions may also represent an increase in misdiagnoses, with many clinicians equating an elevated troponin level with acute MI.¹¹

Although an elevated troponin level is 100% specific for myocardial injury, it is not synonymous with MI.¹² Myocardial injury can be caused by a cardiac condition such as tachyarrhythmia, cardiac trauma, congestive heart failure, ventricular hypertrophy, myocarditis, or pericarditis, or by a noncardiac condition such as sepsis, respiratory failure, pulmonary embolism, pulmonary hypertension, cancer chemotherapy, or renal insufficiency.^4,13 Therefore, to avoid a misdiagnosis of MI, the troponin level must be considered in the clinical context.

In fact, Alcalai et al¹¹ noted that almost half of patients with elevated troponin did not really have an acute coronary syndrome. More importantly, in-hospital and long-term survival rates were significantly better for patients with an acute coronary syndrome than for those without, illustrating the importance of identifying and treating the true disease instead of mislabeling the problem as MI.

Bayesian theory predicts that patients with chest pain who have elevated troponin are less likely to truly have an acute coronary syndrome if the rest of their clinical presentation indicates a low probability for heart disease.¹⁴ Indeed, when McDonald et al¹⁵ used a risk-scoring index based on sex, a history of heart failure or coronary artery disease, the ECG, and use of aspirin, the positive predictive value of an abnormal troponin level was 83% at a risk score of 4 or greater, 63% at a score of 3, 52% at a score of 2, 32% at a score of 1, and 29% at a score of 0.

Thus, cardiac biomarkers are not a substitute for traditional clinical assessment, but rather should be used “in conjunction with the clinical history, physical examination, and interpretation of the ECG.”⁶ Consequently, diagnostic protocols that incorporate pretest clinical features to identify low-risk patients have a higher negative predictive value.

This was illustrated in a study by Than et al¹⁶ that aimed to prospectively validate the safety of an accelerated diagnostic protocol to assess chest pain suggestive of an acute coronary syndrome. The protocol included a structured pretest probability scoring method (ie, the Thrombolysis in Myocardial Infarction [TIMI] score), ECG, and a point-of-care biomarker panel of troponin, creatine kinase MB, and myoglobin. The protocol had a negative predictive value of 99.1%, whereas the use of biomarkers alone had a value of 96.1%.

HISTORY AND PHYSICAL EXAMINATION PROVIDE KEY INFORMATION

In a review, Heidenreich et al⁸ noted certain demographic characteristics associated with worse outcomes—ie, older age and male sex; a history of medical conditions such as diabetes, MI, and hypertension; and heart failure on presentation.

A careful assessment of chest pain and associated symptoms helps narrow the differential diagnosis. Features that increase the likelihood of a cardiac origin of chest pain are:

• Chest pain at the time of presentation (likelihood ratio [LR] = 2.0)
• Radiation of the pain to the right shoulder (LR = 2.9), the left arm (LR = 2.3), or both arms (LR = 7.1)
• Nausea or vomiting (LR = 1.9)
• Diaphoresis (LR = 2.0).¹⁷

The physical examination can detect highrisk features such as new murmurs, hypotension, diaphoresis, pulmonary edema, and rales. It is more specific than sensitive and is useful in identifying low-risk patients by targeting potential noncardiac causes of the patient’s symptoms.¹⁸

The efficacy of clinical assessment was studied in 2,271 patients with chest pain presenting to the emergency department.¹⁹ In this cohort, a low-risk group with a 30-day major cardiovascular event rate (death, MI, stroke, or revascularization) of 2.5% could be identified through the use of the US Agency for Health Care Policy and Research criteria.

Electrocardiography

ECG provides important diagnostic and prognostic information and independently predicts death or MI, even after adjustment for cardiac biomarker measurements,^20,21 making it pivotal in the evaluation.⁴ The key features on ECG that increase the probability of MI are:

• New ST-segment elevation (LR 5.7–53.9)
• New Q waves (LR 5.3–24.8).¹⁷

One study²⁰ found that while the troponin T level was a powerful independent marker in patients presenting with MI, its value for risk stratification was enhanced when it was combined with a standard measure such as ECG.²⁰ While more than 90% of patients with STsegment elevation had an adverse outcome, only 31.7% of those patients had an elevated troponin T level.

No component is sufficient by itself

Thus, in spite of the proliferation of cardiac diagnostic tests, the initial bedside assessment of chest pain remains paramount. In fact, in patients presenting to the emergency department with chest pain, low risk (ie, those with a < 5% probability of MI) may be identified by presenting symptoms, medical history, and ECG alone.¹⁹

Furthermore, although clinical assessment, ECG, and cardiac biomarker testing each provide incremental benefit in assessing chest pain, no component is sufficient by itself. Sanchis et al²² found that even in patients with a normal troponin I level, the risk remained high in the case of ST-segment depression, and that even without signs of ischemia, the probability of cardiac events was 16% when the chest pain score was 11 points or higher.²² Consequently, a normal troponin level, ECG, or any other predictor alone would not ensure a good prognosis.

BIOMARKERS INSTEAD OF STRESS TESTING?

The ACC/AHA guidelines for the diagnosis of patients with unstable angina and non-STsegment elevation MI say that stable patients at low risk with no evidence of ischemia on initial assessment can be admitted to a chest pain unit for observation with serial cardiac biomarkers and ECG.⁴ At the end of the observation period, those who have reassuring results on ECG and normal cardiac biomarker measurements undergo functional cardiac testing or stress testing, or both.⁴

Exercise treadmill testing is a cornerstone of confirmatory testing in an accelerated diagnostic protocol because it is readily available, safe, and easy to do.¹⁸ A low-risk result was shown to have a high negative predictive value,^23,24 so that the likelihood of an acute coronary syndrome is low enough for safe discharge.

However, the overall process is not ideal since it is time-consuming, generates additional costs, and can have false-positive results in patients who are otherwise deemed not to be at high risk. While some studies provided an optimistic view about discharging low-risk patients with negative biomarkers without stress testing,^7,25 others have discouraged omitting exercise treadmill testing from protocols.^22,26

Others have proposed combining a biomarker with an imaging study such as coronary computed tomographic (CT) angiography.²⁷ Normal findings on this study have been shown to have a negative predictive value of up to 100% for ruling out an acute coronary syndrome and the occurrence of major adverse cardiovascular events in the long term.^28,29 Furthermore, it allows more-inclusive assessments of chest pain and can exclude other life-threatening causes such as pulmonary embolism and aortic dissection (referred to as the “triple rule-out”).³⁰

However, 25% to 50% of patients presenting to the emergency department with chest pain may not be candidates for CT angiography because of obesity, contrast allergy, intolerance to beta-blockade, arrhythmia, renal insufficiency, or a history of coronary artery disease.¹⁸ Moreover, it may be more efficient and less costly to discharge some patients without coronary CT angiography³¹ with the help of novel biomarkers without routine additional testing. This may spare patients the additional radiation exposure from CT angiography or nuclear imaging.^27,32

New biomarkers may, it is hoped, better distinguish patients at low risk from those at high risk without resorting to stress testing. Several of these markers are moving toward mainstream clinical use. For a biomarker to be prognostically equivalent to stress testing, it must be able to tell us if the likelihood of an acute coronary syndrome is low enough for safe discharge—ie, it must have a significantly high negative predictive value. Also, it must be an independent predictor of adverse outcomes, particularly in patients deemed at low risk by initial low troponin measurements. Biomarkers that have shown promise in this regard include high-sensitivity troponin, brain-type natriuretic peptide (BNP), cystatin C, and ischemia-modified albumin.

HIGH-SENSITIVITY CARDIAC TROPONIN ASSAYS

Although we speak of “high-sensitivity troponin,” these new assays detect the same molecule as do traditional troponin assays. The difference is that high-sensitivity assays can detect and measure troponin at concentrations much lower than the traditional assays can. In fact, high-sensitivity troponin assays can detect and measure troponin at very low levels in almost all healthy people.

Studies have shown that the high-sensitivity assays have better analytical accuracy and sensitivity than older assays.¹²

Aldous et al³³ reported that, in patients who presented to the emergency department within 4 hours of the onset of chest pain, an elevation in troponin T on a high-sensitivity assay had a positive predictive value of 53.8% and a negative predictive value of 98.3%.

Weber et al³⁴ found the diagnostic value of the high-sensitivity troponin T assay to be superior to that of a contemporary troponin T assay (area under the receiver-operating-characteristics curve [AUC] of 0.949 vs 0.929). Even when the contemporary troponin T assay was negative, the high-sensitivity assay provided strong diagnostic information (AUC 0.81). Furthermore, the high-sensitivity assay provided superior independent prognostic power for death within 6 months.

Hochholzer et al³⁵ reported a prognostic accuracy for death significantly higher (AUC 0.79) than that of contemporary troponin T (AUC 0.69). A concentration of high-sensitivity troponin T above 14 ng/L improved the prediction of death (hazard ratio 2.60) but not of subsequent acute MI in patients with acute chest pain. Therefore, a negative high-sensitivity troponin T assay identifies patients with a good prognosis and who may be discharged without further testing if their clinical presentation and ECG are also reassuring.

Keller et al³⁶ compared the diagnostic performance of the high-sensitivity cardiac troponin I assay against 11 other biomarkers, including a contemporary cardiac troponin I assay. The contemporary troponin I and the high-sensitivity troponin I assays performed best. The high-sensitivity troponin I assay at admission had a sensitivity of 82.3% and a negative predictive value of 94.7% for ruling out acute MI, whereas the contemporary troponin I assay had a sensitivity of 79.4% and a negative predictive value of 94.0%.

Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both troponin I assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value for ruling in acute MI for high-sensitivity cardiac troponin I increased from 75.1% at admission to 95.8% after 3 hours; for the contemporary assay, it increased from 80.9% at admission to 96.1%.³⁶

The authors concluded that performing either of the cardiac troponin I assays 3 hours after admission may help in ruling out MI early on, with a negative predictive value greater than 99%. Moreover, the relative change in concentration within the 3 hours after admission, combined with the 99th percentile diagnostic cutoff value on admission, improves specificity, allowing acute MI to be accurately ruled in.³⁶

Of note, though studies have confirmed that a measurement at 3 hours identifies most cases of MI early, they have not used the recommended maximal sensitivity interval for troponin measurements (6 hours or more).⁶

A proposed algorithm for diagnosing acute MI with a high-sensitivity assay

While high-sensitivity troponin T assays can improve the early diagnosis of acute MI, how best to use them is yet to be defined. They still lack specificity for acute coronary syndromes, with positive predictive values as low as 50%.³⁷

Reichlin et al³⁸ developed and validated an algorithm for rapidly ruling out or ruling in acute MI using a high-sensitivity cardiac troponin T assay, incorporating baseline values and absolute changes within the first hour. Using a baseline threshold of 12 ng/L or less and an absolute change of 3 ng/L or less, they found a sensitivity and negative predictive value of 100%, making these good criteria for ruling out acute MI.

Using a baseline threshold of 60 ng/L or greater and a change from baseline to 1 hour of at least 15 ng/L, the specificity was 97% and the positive predictive value was 84%, making these good criteria for ruling in acute MI.

Patients whose values were in between were classified as being in an “observationalzone group,” in which the prevalence of acute MI was 8%. The cumulative 30-day survival rate was 99.8% in patients in whom the test ruled out MI, 98.6% in the observational-zone patients, and 95.3% in patients in whom the test ruled in MI.³⁸ Using this simple algorithm allowed a safe rule-out as well as an accurate rule-in of acute MI within 1 hour in 77% of unselected patients with acute chest pain; thus, it may obviate the need for prolonged monitoring and serial measurements in three out of four patients.”

Newby³⁹ stated that such an algorithmic approach must be validated in a prospective study that assesses not only sensitivity, negative predictive value, specificity, and positive predictive value, but also the implications for clinical outcomes and the cost of widespread implementation.

In the meantime, clinicians must keep in mind that patient populations in clinical practice are less selected, the prevalence of MI may broadly vary, and confounding comorbidities such as heart failure and renal insufficiency are more common. Studies are also needed to verify whether other factors such as age, sex, and time from symptom onset should be considered.

BRAIN-TYPE NATRIURETIC PEPTIDE

BNP is a 32-amino-acid natriuretic peptide that is released from myocytes. The amount released depends on wall stress brought on by heart failure, ischemic heart disease, or other conditions.

In a study of the diagnostic utility of BNP in the workup of acute chest pain, Haaf et al⁴⁰ found that BNP levels at presentation were significantly higher in patients with acute MI than in patients with other diagnoses. However, the diagnostic accuracy of BNP was lower than that of cardiac troponin T at presentation, though its independent predictive value for all-cause mortality was more accurate than that of troponin T.

Elevation of the BNP ⁴¹ or the N-terminal pro-BNP ^42,43 level was shown to also provide unique prognostic information in patients with suspected and confirmed acute coronary syndrome and was associated with higher rates of short-term and long-term mortality. Therefore, BNP appears useful for the prognosis but not the diagnosis of acute coronary syndromes.

CYSTATIN C

The protein cystatin C, widely used as a biomarker for kidney disease, has more recently been touted as a prognostic marker in acute coronary syndromes.

Jernberg et al⁴⁴ reported that, in patients with a suspected or confirmed acute coronary syndrome, a single measurement of cystatin C significantly improved the early stratification of risk.⁴⁴ Specifically, the cystatin C level was independently associated with mortality risk but not with the risk of subsequent MI.

In another study,⁴⁵ the cystatin C concentration independently predicted the risk of cardiovascular death or MI in non-ST-segment elevation acute coronary syndrome. However, the additive predictive value of cystatin C in these patients was found to be small when clinical risk factors and biomarkers of MI were used in the prediction model. Therefore, cystatin C may predict global risk but does not appear to be useful in diagnosing MI.

ISCHEMIA-MODIFIED ALBUMIN

A major limitation of troponin is that it cannot detect reversible myocardial ischemia in the absence of cardiac necrosis, making stress testing necessary to unmask potential reversible ischemia.

Ischemia-modified albumin has been proposed as a means of detecting cardiac ischemia even if necrosis is absent. It is a product of the N-terminus alteration of albumin caused by myocardial ischemia, which reduces the ability of cobalt to bind to albumin and can be detected with the albumin cobalt binding test. This marker might have a high negative predictive value, ruling out acute coronary syndromes in conditions of low pretest probability with negative necrosis markers and ECG.^13,46

Although ischemia-modified albumin does show promise, doubt remains as to its validity as a biomarker, as its mechanism of generation is not known. Some have suggested that it is in fact a marker of oxidative stress.⁴⁷

PANELS OF MARKERS

The individual biomarkers we have discussed here have advantages and limitations in the emergency workup of chest pain. The concept of using a multimarker panel has been raised as a way of amplifying the positive attributes of individual biomarkers and compensating for their shortcomings.

Sabatine et al⁴⁸ tested this approach in patients with acute coronary syndromes who were at high risk of an adverse outcome. When patients were categorized at presentation on the basis of the number of elevated biomarkers such as cardiac troponin I, C-reactive protein, and BNP, the risk of death nearly doubled with each additional biomarker that was elevated.

The relationship was similar for the end points of MI, heart failure, and the composite at 30 days and 10 months. In a cohort of 1,635 patients, the number of elevated biomarkers remained a predictor of the composite end point after adjustment for known clinical predictors. The risk of death, MI, or heart failure by 6 months was 2.1 times higher in patients with one elevated biomarker, 3.1 times higher in those with two, and 3.7 times higher in those with three.

The authors concluded that a multimarker strategy that categorizes patients on the basis of the number of elevated biomarkers at presentation allows risk-stratification of short- and long-term cardiac events.

Tello-Montoliu et al⁴⁹ tested this idea in patients with non-ST-segment elevation acute coronary syndromes using a panel consisting of cardiac troponin T, C-reactive protein, N-terminal pro-BNP, and fibrin D-dimer. The risk of a major event (death, new acute coronary syndrome, revascularization, or heart failure) at 6 months was associated with abnormal biomarker levels, especially with the presence of three positive biomarkers, even after adjustment for clinical characteristics and ECG findings.

van der Zee et al⁴³ showed that a positive biomarker panel consisting of C-reactive protein and N-terminal pro-BNP identified patients with chest pain and a normal or nondiagnostic ECG who have a high long-term risk of cardiovascular death.

Glaser et al⁵⁰ evaluated the combination of cardiac troponin I, BNP, homocysteine, C-reactive protein, placental growth factor, myeloperoxidase, choline, soluble CD40 ligand, ischemia-modified albumin, and lipoprotein-associated phospholipase A2 in patients with a suspected acute coronary syndrome. The combination of BNP, placental growth factor, and estimated glomerular filtration rate was the most accurate predictor of major adverse cardiovascular events compared with any other biomarker or clinical factor. With appropriate cutoff values, the negative predictive value for a major adverse cardiovascular event at 1 year was as high as 99.1%.

This study highlighted the importance of combining biomarkers, showing that with a negative predictive value of 97% for 30-day events, the combination of placental growth factor, BNP, and cardiac troponin I may help surmount the delay from symptom onset to cardiac troponin increase, thus permitting a more timely diagnosis and safe discharge within 12 hours.

Comment. These studies raise the promise that panels of biomarkers can be used in patients deemed to be at low risk after clinical assessment and troponin evaluation to enable them to be safely discharged early and to obviate the need for stress testing.

If we assume that unstable cardiac disease requiring hospitalization accounts for 35% of patients with chest pain, a hypothetical panel of biomarkers with a sensitivity and specificity of 95% for adverse cardiac outcomes would have a positive predictive value of 91% and a negative predictive value of 97%. The negative likelihood ratio of this hypothetical biomarker panel would be 0.05, while the positive likelihood ratio would be 19. This performance level means that in patients with a pretest probability less than 50%, the posttest probability can be reduced to below 10%, so that such patients can be safely discharged without further hospital evaluation.

Conversely, a positive test result in patients with pretest probability of 30% or greater raises the posttest probability to nearly 90%, meaning that such patients should be considered for aggressive intervention without the need for stress testing.

RETURN TO OUR SCENARIOS

Chest pain remains a nonspecific complaint, and the interpretation of biomarkers to find the cause presents clinicians with challenges, as illustrated by the cases introduced at the beginning of this article.

The cardiac troponin I elevation in scenario 1 led to an initial diagnosis of unstable angina. However, coronary angiography showed lesion-free coronary arteries, thus excluding ischemic heart disease. When other diseases that could cause elevated cardiac troponin I were considered and investigated with further diagnostic tests such as D-dimer, pulmonary embolism became the new working diagnosis, and this was confirmed by CT angiography.

Similarly, given the laboratory values for the patient in scenario 2, the condition could have been mistaken for an acute coronary syndrome. However, the absence of evidence on ECG to support this diagnosis would indicate an erroneously elevated biomarker secondary to his background of chronic renal insufficiency.

Each year in the United States, more than 8 million people come to the emergency department with chest pain, but only a minority are eventually diagnosed with a heart attack.¹

Confronted with signs and symptoms that could represent an acute coronary syndrome, clinicians need to know whether the patient has a benign condition and can safely be sent home or is in urgent need of hospitalization—and they need to do so in a safe, timely, and cost-effective manner.^2,3

Testing for biomarkers of cardiac injury, especially troponins I and T, is an accepted part of the assessment of chest pain. However, the interpretation of these cardiac biomarkers is complicated by the fact they can be elevated from noncoronary causes of chest pain such as pulmonary embolism or renal impairment, and thus should be considered only as part of the patient’s total clinical picture. This uncertainty can result in longer hospital stays and increased testing.

Thus, researchers are searching for new biomarkers that could allow for more rapid and accurate diagnosis and estimation of prognosis.

In this article we will examine the advantages and limitations of measuring cardiac biomarkers. We then discuss the emerging data on new biomarkers, including the very promising high-sensitivity troponin assays, cystatin C, and other markers, and the potential for biomarkers to be used instead of or in combination with stress testing in the evaluation of patients who have no initial evidence of ischemia.

SCENARIO 1: ELEVATED TROPONIN AND ST-SEGMENT ELEVATION

A 46-year-old woman presents to the emergency department with chest pain that started 2 hours earlier. Electrocardiography (ECG) initially shows sinus tachycardia with ST-segment depression and negative T waves in lead aVL. Her cardiac biomarker values (troponin I and creatine kinase MB) are normal. Repeated troponin I measurements show elevations of 250 ng/L, whereas her creatine kinase MB level is within the optimal range. Coronary angiography is unremarkable. Echocardiography shows right ventricular pressure overload in the pulmonary artery and the right ventricle. How should this patient be further evaluated?

SCENARIO 2: ELEVATED TROPONIN AND LEFT VENTRICULAR HYPERTROPHY

A 47-year-old man is admitted with worsening dyspnea and chest pain that worsens with coughing and inspiration. He has a history of end-stage renal disease secondary to poorly controlled hypertension and is being treated with hemodialysis, which he missed for the past 4 weeks while failing to take his hypertension medication. His blood pressure is 270/130 mm Hg. Chest auscultation reveals signs of pulmonary edema—ie, crackles at the end of inspiration. His troponin T level is 394 ng/L. ECG indicates left ventricular hypertrophy. How should this patient be further evaluated?

TROPONIN IS SPECIFIC FOR INJURY, BUT NOT FOR INFARCTION

American College of Cardiology and American Heart Association (ACC/AHA) guidelines⁴ recommend that clinicians ask themselves two questions: what is the likelihood that the patient is truly having an acute coronary syndrome secondary to coronary artery disease, and what is the likelihood of an adverse clinical outcome? Clues come from the initial measurements of biomarkers of cardiac injury, history, physical examination, and ECG (Table 1),⁵ and subsequent care is based on the estimated degree of risk.

Troponin revolutionized the diagnosis and risk stratification of chest pain. The ACC/AHA guidelines call for measuring biomarkers—preferably troponin—in all patients who present with chest discomfort consistent with an acute coronary syndrome.^4,6

Cardiac troponins I and T have been the biomarkers of choice for detecting myocardial injury,^4,6 since elevated concentrations are highly sensitive and tissue-specific.⁷ Moreover, they identify patients at short-term and long-term risk of cardiac events.^4,8

The introduction of troponin testing led to a substantial increase in the rate of diagnosis of myocardial infarction (MI), with an increase in cardiac care unit admissions of more than 20%.^9,10 This was partly because troponin is released into the blood with even minute myocardial damage, so that some patients who previously would have been diagnosed with unstable angina are now found to have non-ST-segment-elevation MI.¹⁰ However, the increase in admissions may also represent an increase in misdiagnoses, with many clinicians equating an elevated troponin level with acute MI.¹¹

Although an elevated troponin level is 100% specific for myocardial injury, it is not synonymous with MI.¹² Myocardial injury can be caused by a cardiac condition such as tachyarrhythmia, cardiac trauma, congestive heart failure, ventricular hypertrophy, myocarditis, or pericarditis, or by a noncardiac condition such as sepsis, respiratory failure, pulmonary embolism, pulmonary hypertension, cancer chemotherapy, or renal insufficiency.^4,13 Therefore, to avoid a misdiagnosis of MI, the troponin level must be considered in the clinical context.

In fact, Alcalai et al¹¹ noted that almost half of patients with elevated troponin did not really have an acute coronary syndrome. More importantly, in-hospital and long-term survival rates were significantly better for patients with an acute coronary syndrome than for those without, illustrating the importance of identifying and treating the true disease instead of mislabeling the problem as MI.

Bayesian theory predicts that patients with chest pain who have elevated troponin are less likely to truly have an acute coronary syndrome if the rest of their clinical presentation indicates a low probability for heart disease.¹⁴ Indeed, when McDonald et al¹⁵ used a risk-scoring index based on sex, a history of heart failure or coronary artery disease, the ECG, and use of aspirin, the positive predictive value of an abnormal troponin level was 83% at a risk score of 4 or greater, 63% at a score of 3, 52% at a score of 2, 32% at a score of 1, and 29% at a score of 0.

Thus, cardiac biomarkers are not a substitute for traditional clinical assessment, but rather should be used “in conjunction with the clinical history, physical examination, and interpretation of the ECG.”⁶ Consequently, diagnostic protocols that incorporate pretest clinical features to identify low-risk patients have a higher negative predictive value.

This was illustrated in a study by Than et al¹⁶ that aimed to prospectively validate the safety of an accelerated diagnostic protocol to assess chest pain suggestive of an acute coronary syndrome. The protocol included a structured pretest probability scoring method (ie, the Thrombolysis in Myocardial Infarction [TIMI] score), ECG, and a point-of-care biomarker panel of troponin, creatine kinase MB, and myoglobin. The protocol had a negative predictive value of 99.1%, whereas the use of biomarkers alone had a value of 96.1%.

HISTORY AND PHYSICAL EXAMINATION PROVIDE KEY INFORMATION

In a review, Heidenreich et al⁸ noted certain demographic characteristics associated with worse outcomes—ie, older age and male sex; a history of medical conditions such as diabetes, MI, and hypertension; and heart failure on presentation.

A careful assessment of chest pain and associated symptoms helps narrow the differential diagnosis. Features that increase the likelihood of a cardiac origin of chest pain are:

• Chest pain at the time of presentation (likelihood ratio [LR] = 2.0)
• Radiation of the pain to the right shoulder (LR = 2.9), the left arm (LR = 2.3), or both arms (LR = 7.1)
• Nausea or vomiting (LR = 1.9)
• Diaphoresis (LR = 2.0).¹⁷

The physical examination can detect highrisk features such as new murmurs, hypotension, diaphoresis, pulmonary edema, and rales. It is more specific than sensitive and is useful in identifying low-risk patients by targeting potential noncardiac causes of the patient’s symptoms.¹⁸

The efficacy of clinical assessment was studied in 2,271 patients with chest pain presenting to the emergency department.¹⁹ In this cohort, a low-risk group with a 30-day major cardiovascular event rate (death, MI, stroke, or revascularization) of 2.5% could be identified through the use of the US Agency for Health Care Policy and Research criteria.

Electrocardiography

ECG provides important diagnostic and prognostic information and independently predicts death or MI, even after adjustment for cardiac biomarker measurements,^20,21 making it pivotal in the evaluation.⁴ The key features on ECG that increase the probability of MI are:

• New ST-segment elevation (LR 5.7–53.9)
• New Q waves (LR 5.3–24.8).¹⁷

One study²⁰ found that while the troponin T level was a powerful independent marker in patients presenting with MI, its value for risk stratification was enhanced when it was combined with a standard measure such as ECG.²⁰ While more than 90% of patients with STsegment elevation had an adverse outcome, only 31.7% of those patients had an elevated troponin T level.

No component is sufficient by itself

Thus, in spite of the proliferation of cardiac diagnostic tests, the initial bedside assessment of chest pain remains paramount. In fact, in patients presenting to the emergency department with chest pain, low risk (ie, those with a < 5% probability of MI) may be identified by presenting symptoms, medical history, and ECG alone.¹⁹

Furthermore, although clinical assessment, ECG, and cardiac biomarker testing each provide incremental benefit in assessing chest pain, no component is sufficient by itself. Sanchis et al²² found that even in patients with a normal troponin I level, the risk remained high in the case of ST-segment depression, and that even without signs of ischemia, the probability of cardiac events was 16% when the chest pain score was 11 points or higher.²² Consequently, a normal troponin level, ECG, or any other predictor alone would not ensure a good prognosis.

BIOMARKERS INSTEAD OF STRESS TESTING?

The ACC/AHA guidelines for the diagnosis of patients with unstable angina and non-STsegment elevation MI say that stable patients at low risk with no evidence of ischemia on initial assessment can be admitted to a chest pain unit for observation with serial cardiac biomarkers and ECG.⁴ At the end of the observation period, those who have reassuring results on ECG and normal cardiac biomarker measurements undergo functional cardiac testing or stress testing, or both.⁴

Exercise treadmill testing is a cornerstone of confirmatory testing in an accelerated diagnostic protocol because it is readily available, safe, and easy to do.¹⁸ A low-risk result was shown to have a high negative predictive value,^23,24 so that the likelihood of an acute coronary syndrome is low enough for safe discharge.

However, the overall process is not ideal since it is time-consuming, generates additional costs, and can have false-positive results in patients who are otherwise deemed not to be at high risk. While some studies provided an optimistic view about discharging low-risk patients with negative biomarkers without stress testing,^7,25 others have discouraged omitting exercise treadmill testing from protocols.^22,26

Others have proposed combining a biomarker with an imaging study such as coronary computed tomographic (CT) angiography.²⁷ Normal findings on this study have been shown to have a negative predictive value of up to 100% for ruling out an acute coronary syndrome and the occurrence of major adverse cardiovascular events in the long term.^28,29 Furthermore, it allows more-inclusive assessments of chest pain and can exclude other life-threatening causes such as pulmonary embolism and aortic dissection (referred to as the “triple rule-out”).³⁰

However, 25% to 50% of patients presenting to the emergency department with chest pain may not be candidates for CT angiography because of obesity, contrast allergy, intolerance to beta-blockade, arrhythmia, renal insufficiency, or a history of coronary artery disease.¹⁸ Moreover, it may be more efficient and less costly to discharge some patients without coronary CT angiography³¹ with the help of novel biomarkers without routine additional testing. This may spare patients the additional radiation exposure from CT angiography or nuclear imaging.^27,32

New biomarkers may, it is hoped, better distinguish patients at low risk from those at high risk without resorting to stress testing. Several of these markers are moving toward mainstream clinical use. For a biomarker to be prognostically equivalent to stress testing, it must be able to tell us if the likelihood of an acute coronary syndrome is low enough for safe discharge—ie, it must have a significantly high negative predictive value. Also, it must be an independent predictor of adverse outcomes, particularly in patients deemed at low risk by initial low troponin measurements. Biomarkers that have shown promise in this regard include high-sensitivity troponin, brain-type natriuretic peptide (BNP), cystatin C, and ischemia-modified albumin.

HIGH-SENSITIVITY CARDIAC TROPONIN ASSAYS

Although we speak of “high-sensitivity troponin,” these new assays detect the same molecule as do traditional troponin assays. The difference is that high-sensitivity assays can detect and measure troponin at concentrations much lower than the traditional assays can. In fact, high-sensitivity troponin assays can detect and measure troponin at very low levels in almost all healthy people.

Studies have shown that the high-sensitivity assays have better analytical accuracy and sensitivity than older assays.¹²

Aldous et al³³ reported that, in patients who presented to the emergency department within 4 hours of the onset of chest pain, an elevation in troponin T on a high-sensitivity assay had a positive predictive value of 53.8% and a negative predictive value of 98.3%.

Weber et al³⁴ found the diagnostic value of the high-sensitivity troponin T assay to be superior to that of a contemporary troponin T assay (area under the receiver-operating-characteristics curve [AUC] of 0.949 vs 0.929). Even when the contemporary troponin T assay was negative, the high-sensitivity assay provided strong diagnostic information (AUC 0.81). Furthermore, the high-sensitivity assay provided superior independent prognostic power for death within 6 months.

Hochholzer et al³⁵ reported a prognostic accuracy for death significantly higher (AUC 0.79) than that of contemporary troponin T (AUC 0.69). A concentration of high-sensitivity troponin T above 14 ng/L improved the prediction of death (hazard ratio 2.60) but not of subsequent acute MI in patients with acute chest pain. Therefore, a negative high-sensitivity troponin T assay identifies patients with a good prognosis and who may be discharged without further testing if their clinical presentation and ECG are also reassuring.

Keller et al³⁶ compared the diagnostic performance of the high-sensitivity cardiac troponin I assay against 11 other biomarkers, including a contemporary cardiac troponin I assay. The contemporary troponin I and the high-sensitivity troponin I assays performed best. The high-sensitivity troponin I assay at admission had a sensitivity of 82.3% and a negative predictive value of 94.7% for ruling out acute MI, whereas the contemporary troponin I assay had a sensitivity of 79.4% and a negative predictive value of 94.0%.

Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both troponin I assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value for ruling in acute MI for high-sensitivity cardiac troponin I increased from 75.1% at admission to 95.8% after 3 hours; for the contemporary assay, it increased from 80.9% at admission to 96.1%.³⁶

The authors concluded that performing either of the cardiac troponin I assays 3 hours after admission may help in ruling out MI early on, with a negative predictive value greater than 99%. Moreover, the relative change in concentration within the 3 hours after admission, combined with the 99th percentile diagnostic cutoff value on admission, improves specificity, allowing acute MI to be accurately ruled in.³⁶

Of note, though studies have confirmed that a measurement at 3 hours identifies most cases of MI early, they have not used the recommended maximal sensitivity interval for troponin measurements (6 hours or more).⁶

A proposed algorithm for diagnosing acute MI with a high-sensitivity assay

While high-sensitivity troponin T assays can improve the early diagnosis of acute MI, how best to use them is yet to be defined. They still lack specificity for acute coronary syndromes, with positive predictive values as low as 50%.³⁷

Reichlin et al³⁸ developed and validated an algorithm for rapidly ruling out or ruling in acute MI using a high-sensitivity cardiac troponin T assay, incorporating baseline values and absolute changes within the first hour. Using a baseline threshold of 12 ng/L or less and an absolute change of 3 ng/L or less, they found a sensitivity and negative predictive value of 100%, making these good criteria for ruling out acute MI.

Using a baseline threshold of 60 ng/L or greater and a change from baseline to 1 hour of at least 15 ng/L, the specificity was 97% and the positive predictive value was 84%, making these good criteria for ruling in acute MI.

Patients whose values were in between were classified as being in an “observationalzone group,” in which the prevalence of acute MI was 8%. The cumulative 30-day survival rate was 99.8% in patients in whom the test ruled out MI, 98.6% in the observational-zone patients, and 95.3% in patients in whom the test ruled in MI.³⁸ Using this simple algorithm allowed a safe rule-out as well as an accurate rule-in of acute MI within 1 hour in 77% of unselected patients with acute chest pain; thus, it may obviate the need for prolonged monitoring and serial measurements in three out of four patients.”

Newby³⁹ stated that such an algorithmic approach must be validated in a prospective study that assesses not only sensitivity, negative predictive value, specificity, and positive predictive value, but also the implications for clinical outcomes and the cost of widespread implementation.

In the meantime, clinicians must keep in mind that patient populations in clinical practice are less selected, the prevalence of MI may broadly vary, and confounding comorbidities such as heart failure and renal insufficiency are more common. Studies are also needed to verify whether other factors such as age, sex, and time from symptom onset should be considered.

BRAIN-TYPE NATRIURETIC PEPTIDE

BNP is a 32-amino-acid natriuretic peptide that is released from myocytes. The amount released depends on wall stress brought on by heart failure, ischemic heart disease, or other conditions.

In a study of the diagnostic utility of BNP in the workup of acute chest pain, Haaf et al⁴⁰ found that BNP levels at presentation were significantly higher in patients with acute MI than in patients with other diagnoses. However, the diagnostic accuracy of BNP was lower than that of cardiac troponin T at presentation, though its independent predictive value for all-cause mortality was more accurate than that of troponin T.

Elevation of the BNP ⁴¹ or the N-terminal pro-BNP ^42,43 level was shown to also provide unique prognostic information in patients with suspected and confirmed acute coronary syndrome and was associated with higher rates of short-term and long-term mortality. Therefore, BNP appears useful for the prognosis but not the diagnosis of acute coronary syndromes.

CYSTATIN C

The protein cystatin C, widely used as a biomarker for kidney disease, has more recently been touted as a prognostic marker in acute coronary syndromes.

Jernberg et al⁴⁴ reported that, in patients with a suspected or confirmed acute coronary syndrome, a single measurement of cystatin C significantly improved the early stratification of risk.⁴⁴ Specifically, the cystatin C level was independently associated with mortality risk but not with the risk of subsequent MI.

In another study,⁴⁵ the cystatin C concentration independently predicted the risk of cardiovascular death or MI in non-ST-segment elevation acute coronary syndrome. However, the additive predictive value of cystatin C in these patients was found to be small when clinical risk factors and biomarkers of MI were used in the prediction model. Therefore, cystatin C may predict global risk but does not appear to be useful in diagnosing MI.

ISCHEMIA-MODIFIED ALBUMIN

A major limitation of troponin is that it cannot detect reversible myocardial ischemia in the absence of cardiac necrosis, making stress testing necessary to unmask potential reversible ischemia.

Ischemia-modified albumin has been proposed as a means of detecting cardiac ischemia even if necrosis is absent. It is a product of the N-terminus alteration of albumin caused by myocardial ischemia, which reduces the ability of cobalt to bind to albumin and can be detected with the albumin cobalt binding test. This marker might have a high negative predictive value, ruling out acute coronary syndromes in conditions of low pretest probability with negative necrosis markers and ECG.^13,46

Although ischemia-modified albumin does show promise, doubt remains as to its validity as a biomarker, as its mechanism of generation is not known. Some have suggested that it is in fact a marker of oxidative stress.⁴⁷

PANELS OF MARKERS

The individual biomarkers we have discussed here have advantages and limitations in the emergency workup of chest pain. The concept of using a multimarker panel has been raised as a way of amplifying the positive attributes of individual biomarkers and compensating for their shortcomings.

Sabatine et al⁴⁸ tested this approach in patients with acute coronary syndromes who were at high risk of an adverse outcome. When patients were categorized at presentation on the basis of the number of elevated biomarkers such as cardiac troponin I, C-reactive protein, and BNP, the risk of death nearly doubled with each additional biomarker that was elevated.

The relationship was similar for the end points of MI, heart failure, and the composite at 30 days and 10 months. In a cohort of 1,635 patients, the number of elevated biomarkers remained a predictor of the composite end point after adjustment for known clinical predictors. The risk of death, MI, or heart failure by 6 months was 2.1 times higher in patients with one elevated biomarker, 3.1 times higher in those with two, and 3.7 times higher in those with three.

The authors concluded that a multimarker strategy that categorizes patients on the basis of the number of elevated biomarkers at presentation allows risk-stratification of short- and long-term cardiac events.

Tello-Montoliu et al⁴⁹ tested this idea in patients with non-ST-segment elevation acute coronary syndromes using a panel consisting of cardiac troponin T, C-reactive protein, N-terminal pro-BNP, and fibrin D-dimer. The risk of a major event (death, new acute coronary syndrome, revascularization, or heart failure) at 6 months was associated with abnormal biomarker levels, especially with the presence of three positive biomarkers, even after adjustment for clinical characteristics and ECG findings.

van der Zee et al⁴³ showed that a positive biomarker panel consisting of C-reactive protein and N-terminal pro-BNP identified patients with chest pain and a normal or nondiagnostic ECG who have a high long-term risk of cardiovascular death.

Glaser et al⁵⁰ evaluated the combination of cardiac troponin I, BNP, homocysteine, C-reactive protein, placental growth factor, myeloperoxidase, choline, soluble CD40 ligand, ischemia-modified albumin, and lipoprotein-associated phospholipase A2 in patients with a suspected acute coronary syndrome. The combination of BNP, placental growth factor, and estimated glomerular filtration rate was the most accurate predictor of major adverse cardiovascular events compared with any other biomarker or clinical factor. With appropriate cutoff values, the negative predictive value for a major adverse cardiovascular event at 1 year was as high as 99.1%.

This study highlighted the importance of combining biomarkers, showing that with a negative predictive value of 97% for 30-day events, the combination of placental growth factor, BNP, and cardiac troponin I may help surmount the delay from symptom onset to cardiac troponin increase, thus permitting a more timely diagnosis and safe discharge within 12 hours.

Comment. These studies raise the promise that panels of biomarkers can be used in patients deemed to be at low risk after clinical assessment and troponin evaluation to enable them to be safely discharged early and to obviate the need for stress testing.

If we assume that unstable cardiac disease requiring hospitalization accounts for 35% of patients with chest pain, a hypothetical panel of biomarkers with a sensitivity and specificity of 95% for adverse cardiac outcomes would have a positive predictive value of 91% and a negative predictive value of 97%. The negative likelihood ratio of this hypothetical biomarker panel would be 0.05, while the positive likelihood ratio would be 19. This performance level means that in patients with a pretest probability less than 50%, the posttest probability can be reduced to below 10%, so that such patients can be safely discharged without further hospital evaluation.

Conversely, a positive test result in patients with pretest probability of 30% or greater raises the posttest probability to nearly 90%, meaning that such patients should be considered for aggressive intervention without the need for stress testing.

RETURN TO OUR SCENARIOS

Chest pain remains a nonspecific complaint, and the interpretation of biomarkers to find the cause presents clinicians with challenges, as illustrated by the cases introduced at the beginning of this article.

The cardiac troponin I elevation in scenario 1 led to an initial diagnosis of unstable angina. However, coronary angiography showed lesion-free coronary arteries, thus excluding ischemic heart disease. When other diseases that could cause elevated cardiac troponin I were considered and investigated with further diagnostic tests such as D-dimer, pulmonary embolism became the new working diagnosis, and this was confirmed by CT angiography.

Similarly, given the laboratory values for the patient in scenario 2, the condition could have been mistaken for an acute coronary syndrome. However, the absence of evidence on ECG to support this diagnosis would indicate an erroneously elevated biomarker secondary to his background of chronic renal insufficiency.

Although long considered a disease of elderly men, cardiovascular disease is increasingly recognized for its impact on women. In fact, it is now the leading cause of death in women worldwide, and in the United States more women than men die of it.¹

Given this epidemic of cardiovascular disease in women, more research is now being dedicated to identifying sex-specific aspects of cardiovascular disease, the better to prevent and treat it.

This review will focus on the most recent information about how prevention, symptoms, and underlying cardiovascular conditions differ in women.

PRIMARY PREVENTION: ONGOING DEBATE

Women who diet, exercise, and abstain from smoking have an 80% lower rate of cardiovascular events than the female population overall.² However, beyond lifestyle modification and blood pressure control, there is ongoing debate as to the efficacy of our available therapies for preventing cardiovascular disease in women.

Aspirin for primary prevention in women: No benefit?

The use of aspirin to prevent cardiovascular disease in women has long been controversial. Several trials showed a lower rate of myocardial infarction in people using aspirin for primary prevention, but most of the patients in the initial trials were men (Table 1).³

The Women’s Health Study⁴ assigned 39,876 women age 45 and older to receive either aspirin (100 mg on alternate days) or placebo, and monitored them for more than 10 years for major cardiovascular events (non-fatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes).

The results, published in 2005, showed that the rates of myocardial infarction and cardiovascular death were not significantly lower in the aspirin group, although the rate of ischemic stroke was 24% lower. There were more hemorrhagic strokes in the aspirin group (not statistically significant), and there was significantly more gastrointestinal bleeding. The study showed the relative risk (RR) and 95% confidence interval (CI) for several outcomes in aspirin users were:

• Myocardial infarction—RR 1.02, 95% CI 0.84–1.25, P = .83
• Cardiovascular death—RR 0.95, 95% CI 0.74–1.22, P = .68
• Ischemic stroke—RR 0.76, 95% CI 0.63–0.93, P = .009
• Hemorrhagic stroke—RR 1.24, 95% CI 0.82–1.87, P = .31
• Gastrointestinal bleeding—RR 1.4, 95% CI 1.07–1.83, P = .02.

A later analysis indicated that noncompliance had no effect on these results.⁵

However, a subgroup analysis of women over age 65 found a significant reduction in the rate of myocardial infarction and in the composite end point of myocardial infarction, stroke, and cardiovascular death, although there was a trend toward a higher rate of gastrointestinal bleeding. The numbers in aspirin users in the subgroup over age 65 were as follows:

• Myocardial infarction—RR 0.66, 95% CI 0.44–0.97, P = .04
• Composite end point—RR 0.74, 95% CI 0.59–0.92, P = .008.

Aspirin was taken every other day and at a higher dose than the 81 mg recommended in the United States, although it is unclear how these differences may have affected the results.

United States Preventive Services Task Force (USPSTF) recommendations. Although the USPSTF currently recommends aspirin for men age 45 to 79 to prevent myocardial infarction, it offers no such recommendation for women, largely because of the results of the Women’s Health Initiative study. However, it does recommend aspirin to prevent ischemic stroke in women age 55 to 79.³ Additionally, aspirin can be considered for prevention of myocardial infarction in women who are over age 65 or at high risk.⁶

This is based on Women’s Health Study data for women over age 65 showing a number needed to treat of 47 to prevent 1 cardiovascular event, whereas the number needed to harm, defined by a major hemorrhagic event, was 128. In contrast, in women younger than age 65, the number needed to treat was 2,001 and the number needed to harm was 196.⁴

High-risk features, as defined by the guidelines, are a history of coronary artery disease, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes, or chronic kidney disease, or a 10-year predicted risk of cardiovascular disease of more than 10%.

Jardine et al⁷ reported that aspirin was beneficial in patients with chronic kidney disease. The rates of cardiovascular death, death from any cause, and stroke were significantly lower in patients with a glomerular filtration rate (GFR) less than 45 mL/min if they received aspirin. The rates were also lower in aspirin recipients with a GFR between 46 and 60 mL/min, but the difference was not statistically significant.

Comments. Given the risk of significant gastrointestinal bleeding and a trend toward hemorrhagic stroke with aspirin use,⁴ it is important to weigh the risks and benefits of aspirin for primary prevention in women.

Our understanding of the reasons for sex differences in the clinical benefits of aspirin for primary prevention is limited at this point. Studies have shown a higher prevalence of platelet reactivity and aspirin resistance in women than in men, suggesting that hormonal differences may play a role.⁸ There has been mention of using higher doses of aspirin in women to achieve the same level of platelet inhibition as in men. However, studies have shown essentially equal platelet inhibition in both men and women after aspirin administration.⁹ Therefore, more work needs to be done to better understand the observed sex differences in response to aspirin.

Given suggestions that statins may not be effective in women¹⁰ and the fact that women were underrepresented in earlier statin trials, a number of studies have examined this issue in the last several years.

The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin)¹⁰ enrolled patients who had no history of coronary artery disease and who had a C-reactive protein level equal to or greater than 2 mg/L and a low-density lipoprotein cholesterol level of less than 130 mg/dL. (Of note, these patients would not have met the criteria for receiving a statin for primary prevention according to the current Adult Treatment Panel guidelines.)

The women in the trial who received rosuvastatin had a 46% lower incidence of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes. In addition, a meta-analysis performed by the authors showed a one-third reduction of cardiovascular disease end points in women. However, there was no reduction in the mortality rate.

Reprinted from Kostis WJ, et al. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59:572–582, with permission from Elsevier.

Other statin trials. A later meta-analysis of randomized primary prevention trials found that men and women derived similar benefit from statins in terms of cardiovascular disease end points and all-cause mortality (Figure 1),¹¹ although five of the trials included a small number of secondary prevention patients. In contrast, a meta-analysis of only primary prevention patients showed no benefit of statin therapy in all-cause mortality, although the authors acknowledged that there were insufficient data to look specifically at women in this sample.¹²

A Cochrane review conducted before the JUPITER data were available concluded that there was insufficient evidence to prescribe statins for primary prevention in patients at low cardiovascular risk.13 However, an updated version that included results of the JUPITER trial concluded that there was a reduction in the rate of all-cause mortality and cardiovascular events in both men and women receiving a statin for primary prevention.14

Given these conflicting results, debate continues as to the benefit of statins for primary prevention, not only in women but in the population as a whole.^15,16 The definition of high risk, in terms of comorbidities and lipid profile, also continues to evolve and will likely be an important factor in identifying women who will benefit from statin therapy for primary prevention.

Statin adverse effects. Much of the debate about statins for primary prevention stems from concern about the adverse effects of these drugs. In addition to myopathy, there have been reports of increased risks of new diabetes and cognitive impairment.¹⁶ In a post hoc analysis of the Women’s Health Initiative, the adjusted risk of diabetes was 48% higher in women taking a statin for primary prevention than in similar women not taking a statin.¹⁷ (This finding should be viewed with caution, since the data are observational.)

There has also been a question of whether women experience more side effects from statin therapy than men do. Although thin or frail women over age 80 are more susceptible to statin side effects, this finding has not been observed in younger women.¹⁸

Comment. In view of the data, it appears reasonable to consider statin therapy for primary prevention in women deemed to be at high risk based on the current guidelines. However, as always, one must consider whether the benefits outweigh the risks for the individual patient. More study is needed to better evaluate the utility of statin therapy in primary prevention.

Hormone therapy

Hormone therapy has received enormous attention in both the medical community and the public media. (Hormone therapy is either combined estrogen and progestin or estrogen alone, used to treat symptoms of menopause and to prevent osteoporosis in postmenopausal women. Here, we will discuss hormone therapy and not hormone replacement therapy, which is used specifically to treat premature menopause.)

The safety of estrogen-progestin combination therapy has been the subject of great debate since a Women’s Health Initiative study showed a trend toward a greater risk of cardiovascular disease in estrogen-progestin users.¹⁹

Women who received estrogen by itself showed no difference in cardiovascular risk compared with those who received placebo. Unopposed estrogen is rarely prescribed, since it increases the risk of endometrial cancer in women who have not undergone hysterectomy.²⁰

Both unopposed estrogen and combination therapy have also been found to increase the risk of stroke,²⁰ deep vein thrombosis, gallbladder disease, and certain forms of urinary incontinence.

Guidelines on hormone therapy. The USPSTF does not recommend hormone therapy to prevent chronic conditions, basing its decision on the findings from the Women’s Health Initiative.²¹ The American College of Cardiology and American Heart Association (ACC/AHA) 2007 guidelines advise against continuing hormone therapy in patients who present with acute coronary syndrome, although recommendations need to address a broader scope of primary and secondary prevention patients.

Does timing matter? There is a hypothesis that when hormone therapy is started may affect the cardiovascular risk. A secondary analysis of the Women’s Health Initiative study²² showed a trend towards less cardiovascular disease in women who started hormone therapy within 9 years of menopause, whereas those starting it later had a statistically significantly higher rate of cardiovascular mortality. However, all women had a higher risk of stroke while on hormone therapy, regardless of timing.²²

A study of 1,006 healthy women age 45 to 58 whose last menstrual period was 3 to 24 months before enrollment found a statistically significant reduction in the composite end point of death, hospital admission for myocardial infarction, or heart failure with hormone therapy.²³ There was no significant increase in breast cancer, deep vein thrombosis, or stroke after 10 years of randomized treatment.

A retrospective analysis of 71,237 postmenopausal women in the California Teachers Study also found a significant reduction in the rate of cardiovascular disease-related deaths with hormone therapy in younger women (ie, younger than age 65), but not in older women.²⁴ The authors concluded that it may not just be the years after menopause but also the baseline age of the woman that may influence outcomes.

In view of these studies, there is increasing recognition that hormone therapy may, in fact, still be beneficial in terms of cardiovascular and all-cause mortality in carefully selected patients. The cardiovascular risk in women, specifically older women who have had a longer duration of menopause, should also be weighed against the potential benefits of therapy in terms of quality of life and symptom relief.

Trials under way include the Kronos Early Estrogen Prevention (KEEP) and Danish Osteoporosis Prevention (DOPS) studies. KEEP is a 4-year, double-blind, randomized controlled trial of hormone therapy in women within 3 years of menopause. DOPS is an open-label trial that includes more than 1,000 women with early menopause. The results of these trials will likely affect future recommendations.

WOMEN’S SYMPTOMS: TYPICAL OR ATYPICAL?

Whether the presenting symptoms of acute coronary syndromes differ between men and women has been much debated.

More women than men seem to present with atypical symptoms.^25–27 (The term “atypical” refers to symptoms that do not include the three classic components of angina: substernal chest pain or discomfort, provoked by exertion or emotional stress, and relieved by rest or nitroglycerin, or both.²⁸)

However, most women still present with chest pain. In a study by Dey et al,²⁶ 92% of the 7,638 women with presumed acute coronary syndrome presented with chest pain. In women who had atypical symptoms, dyspnea, nausea, vomiting, and diaphoresis were the most common symptoms. Women were significantly more likely than men to present with nausea and vomiting (32% vs 23%, P = .001).

Women in the study were also more likely to have angiographically normal coronary arteries (12% vs 6%, P < .001).²⁶ This difference may be largely due to noncardiac chest pain, but it may also represent conditions such as vasospasm, microvascular disease, or stress cardiomyopathy, all of which disproportionately affect women.

An earlier review of 10 major studies found a higher percentage of women presenting with atypical symptoms (37.5% of women vs 27.4% of men).²⁵ However, symptoms were not a focus of these studies, and the findings may therefore be skewed by inaccurate documentation.

Atypical warning signs. Although most women with acute coronary syndrome present acutely with chest pain, women may have different warning signs than men. Only about one-third of women experience angina before presentation.²⁹ Compared with men, women are more likely to complain of shortness of breath, fatigue, and weakness leading up to a diagnosis of a myocardial infarction.²⁹ Therefore, the prodromal symptoms of cardiovascular disease may in fact be significantly more atypical in women than in men, suggesting the need for heightened vigilance in the cardiovascular evaluation of women who have nonanginal symptoms.

THE ROLE OF STRESS TESTING IN WOMEN

Stress testing in various forms continues to be widely used in the diagnosis of heart disease in women, although data are scarce regarding its utility in women.

The ACC/AHA guidelines continue to recommend exercise stress electrocardiography (ECG) for women who have symptoms, are at intermediate risk, and have a normal result on resting ECG.³⁰

Exercise ECG has a higher false-positive rate in women than in men,³¹ and there appears to be no relationship between exercise-induced ST-segment depression and the rate of cardiovascular mortality or all-cause mortality in women.^32,33 On the other hand, exercise ECG yields valuable additional information such as exercise capacity, chronotropic response, heart-rate recovery, and blood pressure response, all of which have important diagnostic and prognostic implications in women.³⁴

For those who have an abnormal resting ECG, the addition of an imaging test, ie, echocardiography or single-photon emission computed tomography (SPECT), is indicated. Both have limitations: SPECT can give false-positive results because of breast attenuation, and echocardiography varies in accuracy depending on the quality of acoustic windows obtained. Both exercise stress SPECT and exercise stress ECG have higher sensitivity and specificity than electrocardiographic exercise stress testing alone,³⁴ and there is evidence that the two imaging tests are comparable in women.³⁵

In those women who have baseline left bundle branch block or who cannot exercise, a pharmacologic stress test should be performed. Of course, this is a less desirable testing method, given the loss of valuable information obtained from exercising the patient.

UNDERLYING CONDITIONS THAT DISPROPORTIONATELY AFFECT WOMEN

Microvascular angina

Perimenopausal and postmenopausal women account for 70% of patients presenting with chest pain and elevated cardiac enzymes but no significant angiographic evidence of coronary artery disease.³⁶ This condition, commonly called syndrome X, is often characterized by lingering, dull chest pain after exertion and is seen more frequently in women younger than those presenting with classic cardiovascular disease.

Because at least some of these patients show evidence of ST-segment depression and reversible perfusion defects on imaging, the condition is thought to be caused by ischemia of the microvascular bed leading to microvascular angina.³⁷

Although this is still an area of research, microvascular dysfunction has recently been proposed as an explanation for these findings. Abnormal vasoconstriction and impaired vasodilation of the microvascular bed, insulin resistance, increased systemic inflammation, and abnormal pain response have all been cited as potentially contributing to microvascular dysfunction.³⁶

Estrogen deficiency is thought to play a central role in the significantly increased burden of microvascular dysfunction seen in women, with some studies suggesting that hormone therapy can relieve symptoms. However, given the concerns about adverse cardiovascular outcomes in women on hormone therapy, there has been little investigation of this treatment for this disorder.

Studies have shown worse cardiovascular outcomes and higher rates of angina-related hospitalization and repeat heart catheterizations in women with microvascular dysfunction.³⁸

Diagnosing microvascular angina must be done indirectly, as there is no safe and minimally invasive technique by which to directly observe the microvasculature. Current coronary angiographic techniques cannot image vessels smaller than 0.5 mm in diameter, and endomyocardial biopsy cannot access the larger periarterioles thought to play a major role in regulating coronary blood flow.³⁹

Image courtesy of Dr. Deborah Kwon

Because the coronary microvasculature controls total coronary resistance and therefore regulates myocardial blood flow, measuring myocardial blood flow at maximum vasodilation, termed coronary flow reserve, can indirectly evaluate the degree of microvascular dysfunction.⁴⁰ In the absence of obstructive epicardial coronary disease, noninvasive imaging techniques or provocative testing in the coronary catheterization lab can be used for this purpose. In terms of noninvasive imaging, perfusion magnetic resonance imaging (Figure 2) or positron emission tomography is often performed.⁴⁰

Coronary flow reserve can also be measured by invasive means in the catheterization laboratory after maximum hyperemia is induced by adenosine or other such vasodilatory agents.⁴¹ However, measurements obtained in this invasive manner are greatly affected by hemodynamic changes and can have poor reproducibility.⁴⁰

Proposed therapy for microvascular angina. Once a diagnosis has been made, lifestyle modification, antianginal agents, angiotensin-converting enzyme inhibitors, and statins have been suggested for therapy.³⁹ Pain management techniques are also used, given the increased pain sensitivity observed in women with this condition. However, no therapy to date has proven overwhelmingly effective in these patients, and a disproportionate number of women suffer from chronic symptoms despite these treatments. Currently, researchers are looking for new agents to treat microvascular disease.

Stress cardiomyopathy

Images courtesy of Dr. Michael Faulx and Dr. Shikhar Agarwal

Stress cardiomyopathy, also called takotsubo cardiomyopathy or “broken heart syndrome,” is another condition that disproportionately affects postmenopausal women. It is often associated with sudden emotional or physical stress. Patients present with signs and symptoms of myocardial infarction without demonstrable epicardial coronary artery disease. The hallmark of stress cardiomyopathy is left ventricular dysfunction, often severe, with classic apical ballooning that resembles a Japanese fishing pot (takotsubo) used to trap octopuses, hence the name (Figure 3).

According to a review by Akashi et al⁴² based on previously reported Mayo Clinic criteria, the diagnosis of stress cardiomyopathy includes each of the following:

• Transient hypokinesis, akinesis, or dyskinesis in the left ventricular midsegments with or without apical involvement; regional wall-motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful trigger
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture
• New abnormality on ECG (eg, ST-segment elevation, T-wave inversion) or modest elevation in cardiac troponin
• Absence of pheochromocytoma or myocarditis.

From 80% to 100% of reported cases are in women, with an average age range of 61 to 76.⁴² It is unclear why there is such an overwhelming postmenopausal female preponderance of the disease. Studies have implicated estrogen deficiency, as it appears to attenuate the levels of cardioprotective substances in the body that in part regulate catecholamine surges and may also increase the level of oxidative stress.⁴²

Several mechanisms for this condition have been proposed. The condition may be caused by multivessel epicardial coronary spasm or spontaneously resolved plaque rupture, resulting in stunned myocardium. However, the regional distribution of wall-motion abnormality is often out of proportion to the level of cardiac enzyme elevation, and in the case of plaque rupture, is frequently not consistent with a single coronary vessel.⁴² A catecholamine surge causing myocardial and neurogenic stunning has also been proposed, although many of these patients have normal catecholamine levels.⁴² Finally, microvascular dysfunction has been found in a number of patients with this condition. However, it is difficult to establish a causal relationship, since apical ballooning could result in microvascular dysfunction.⁴²

Treatment of stress cardiomyopathy has not been standardized, in part because the left ventricular dysfunction often resolves spontaneously within several weeks.^43,44 Given the proposed catecholaminergic mechanism, some experts believe that beta-blockers are contraindicated because of the resulting unopposed activation of alpha-adrenoreceptors. However, this continues to be a matter of debate. There is also no clear indication for other standard therapies for acute coronary syndrome such as aspirin and heparin, and their use appears to vary in clinical practice.

Although most patients improve with time and recurrence is exceedingly rare, it should be emphasized that they may present acutely with severe hemodynamic instability and cardiogenic shock. Therefore, advanced means of support, such as an intra-aortic balloon pump, may be indicated until the patient recovers from the acute phase of the disease.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome resulting from dissection of the coronary intimal or medial layer and associated hematoma formation, leading to coronary occlusion.^45,46 In a case series of 87 patients, 49% presented with an ST-segment elevation myocardial infarction, and 23% were found to have multivessel SCAD.⁴⁶

SCAD occurs predominantly in young, healthy women (mean age 30–45 years). Approximately 70% of cases are in women, 30% of whom are in the peripartum period.⁴⁵ The reasons for the increased risk during pregnancy have not yet been elucidated, but changing sex hormones, increased cardiac output and shear stress, and an increased inflammatory response have been implicated.⁴⁵

Diagnosing SCAD. Coronary angiography should be performed with extreme caution in patients suspected of having SCAD, given the risk of further dissection of the artery with forceful injections. In certain cases, it may be difficult to detect SCAD on routine angiography if there is no communication between the true and false lumen.

If the suspicion for SCAD is high, intravascular ultrasonography or optical coherence tomography can be used to better evaluate the vessel.⁴⁵ Although optical coherence tomography has greater spatial resolution, it is more costly and is not as widely used as intravascular ultrasonography in the clinical setting

Managing SCAD. Although conservative management and coronary artery bypass grafting have been shown to cause minimal in-hospital morbidity, percutaneous coronary intervention has been complicated by technical failure in up to 35% of patients in one series.⁴⁶

While there is no standardized way to manage these patients, experts currently recommend conservative management with standard therapies for acute coronary syndrome (Figure 4). Although antithrombotic agents can decrease thrombus burden, they must be used with caution, because they also increase the risk of bleeding into the false lumen.

If patients experience recurrent or ongoing ischemia despite conservative management, then revascularization should be considered. Optical coherence tomography or intravascular ultrasonography is recommended to ensure proper stent alignment and positioning.

Coronary artery bypass grafting could be considered in preference to percutaneous coronary intervention, given that the former appears to be safer,⁴⁶ although this requires further investigation. Some studies have cautioned against using fibrinolytic therapy, based on anecdotal evidence that it may further propagate the dissection,⁴⁵ although this therapy has been used in other case studies.⁴⁶

While mortality rates are relatively low (95% survival at 2 years),⁴⁵ the estimated risk of recurrent SCAD at 10 years is approximately 30%.⁴⁶

Image courtesy of Dr. Heather Gornik

Associated with fibromuscular dysplasia. Of note, a sizeable number of patients with SCAD have been found to have fibromuscular dysplasia. This is a nonatherosclerotic, noninflammatory vascular condition that can affect any vascular bed in the body, although there is a predilection for the renal and carotid arteries (Figure 5).⁴⁷ Fibromuscular dysplasia also disproportionately affects women and appears to be a concomitant condition in the majority of patients with SCAD.⁴⁷ Imaging of the carotid and renal arteries of patients with SCAD has revealed a number of cases of fibromuscular dysplasia.^46,48 This noted association will likely allow for ongoing research to better understand the pathophysiology of these two conditions.

Although long considered a disease of elderly men, cardiovascular disease is increasingly recognized for its impact on women. In fact, it is now the leading cause of death in women worldwide, and in the United States more women than men die of it.¹

Given this epidemic of cardiovascular disease in women, more research is now being dedicated to identifying sex-specific aspects of cardiovascular disease, the better to prevent and treat it.

This review will focus on the most recent information about how prevention, symptoms, and underlying cardiovascular conditions differ in women.

PRIMARY PREVENTION: ONGOING DEBATE

Women who diet, exercise, and abstain from smoking have an 80% lower rate of cardiovascular events than the female population overall.² However, beyond lifestyle modification and blood pressure control, there is ongoing debate as to the efficacy of our available therapies for preventing cardiovascular disease in women.

Aspirin for primary prevention in women: No benefit?

The use of aspirin to prevent cardiovascular disease in women has long been controversial. Several trials showed a lower rate of myocardial infarction in people using aspirin for primary prevention, but most of the patients in the initial trials were men (Table 1).³

The Women’s Health Study⁴ assigned 39,876 women age 45 and older to receive either aspirin (100 mg on alternate days) or placebo, and monitored them for more than 10 years for major cardiovascular events (non-fatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes).

The results, published in 2005, showed that the rates of myocardial infarction and cardiovascular death were not significantly lower in the aspirin group, although the rate of ischemic stroke was 24% lower. There were more hemorrhagic strokes in the aspirin group (not statistically significant), and there was significantly more gastrointestinal bleeding. The study showed the relative risk (RR) and 95% confidence interval (CI) for several outcomes in aspirin users were:

• Myocardial infarction—RR 1.02, 95% CI 0.84–1.25, P = .83
• Cardiovascular death—RR 0.95, 95% CI 0.74–1.22, P = .68
• Ischemic stroke—RR 0.76, 95% CI 0.63–0.93, P = .009
• Hemorrhagic stroke—RR 1.24, 95% CI 0.82–1.87, P = .31
• Gastrointestinal bleeding—RR 1.4, 95% CI 1.07–1.83, P = .02.

A later analysis indicated that noncompliance had no effect on these results.⁵

However, a subgroup analysis of women over age 65 found a significant reduction in the rate of myocardial infarction and in the composite end point of myocardial infarction, stroke, and cardiovascular death, although there was a trend toward a higher rate of gastrointestinal bleeding. The numbers in aspirin users in the subgroup over age 65 were as follows:

• Myocardial infarction—RR 0.66, 95% CI 0.44–0.97, P = .04
• Composite end point—RR 0.74, 95% CI 0.59–0.92, P = .008.

Aspirin was taken every other day and at a higher dose than the 81 mg recommended in the United States, although it is unclear how these differences may have affected the results.

United States Preventive Services Task Force (USPSTF) recommendations. Although the USPSTF currently recommends aspirin for men age 45 to 79 to prevent myocardial infarction, it offers no such recommendation for women, largely because of the results of the Women’s Health Initiative study. However, it does recommend aspirin to prevent ischemic stroke in women age 55 to 79.³ Additionally, aspirin can be considered for prevention of myocardial infarction in women who are over age 65 or at high risk.⁶

This is based on Women’s Health Study data for women over age 65 showing a number needed to treat of 47 to prevent 1 cardiovascular event, whereas the number needed to harm, defined by a major hemorrhagic event, was 128. In contrast, in women younger than age 65, the number needed to treat was 2,001 and the number needed to harm was 196.⁴

High-risk features, as defined by the guidelines, are a history of coronary artery disease, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes, or chronic kidney disease, or a 10-year predicted risk of cardiovascular disease of more than 10%.

Jardine et al⁷ reported that aspirin was beneficial in patients with chronic kidney disease. The rates of cardiovascular death, death from any cause, and stroke were significantly lower in patients with a glomerular filtration rate (GFR) less than 45 mL/min if they received aspirin. The rates were also lower in aspirin recipients with a GFR between 46 and 60 mL/min, but the difference was not statistically significant.

Comments. Given the risk of significant gastrointestinal bleeding and a trend toward hemorrhagic stroke with aspirin use,⁴ it is important to weigh the risks and benefits of aspirin for primary prevention in women.

Our understanding of the reasons for sex differences in the clinical benefits of aspirin for primary prevention is limited at this point. Studies have shown a higher prevalence of platelet reactivity and aspirin resistance in women than in men, suggesting that hormonal differences may play a role.⁸ There has been mention of using higher doses of aspirin in women to achieve the same level of platelet inhibition as in men. However, studies have shown essentially equal platelet inhibition in both men and women after aspirin administration.⁹ Therefore, more work needs to be done to better understand the observed sex differences in response to aspirin.

Given suggestions that statins may not be effective in women¹⁰ and the fact that women were underrepresented in earlier statin trials, a number of studies have examined this issue in the last several years.

The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin)¹⁰ enrolled patients who had no history of coronary artery disease and who had a C-reactive protein level equal to or greater than 2 mg/L and a low-density lipoprotein cholesterol level of less than 130 mg/dL. (Of note, these patients would not have met the criteria for receiving a statin for primary prevention according to the current Adult Treatment Panel guidelines.)

The women in the trial who received rosuvastatin had a 46% lower incidence of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes. In addition, a meta-analysis performed by the authors showed a one-third reduction of cardiovascular disease end points in women. However, there was no reduction in the mortality rate.

Reprinted from Kostis WJ, et al. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59:572–582, with permission from Elsevier.

Other statin trials. A later meta-analysis of randomized primary prevention trials found that men and women derived similar benefit from statins in terms of cardiovascular disease end points and all-cause mortality (Figure 1),¹¹ although five of the trials included a small number of secondary prevention patients. In contrast, a meta-analysis of only primary prevention patients showed no benefit of statin therapy in all-cause mortality, although the authors acknowledged that there were insufficient data to look specifically at women in this sample.¹²

A Cochrane review conducted before the JUPITER data were available concluded that there was insufficient evidence to prescribe statins for primary prevention in patients at low cardiovascular risk.13 However, an updated version that included results of the JUPITER trial concluded that there was a reduction in the rate of all-cause mortality and cardiovascular events in both men and women receiving a statin for primary prevention.14

Given these conflicting results, debate continues as to the benefit of statins for primary prevention, not only in women but in the population as a whole.^15,16 The definition of high risk, in terms of comorbidities and lipid profile, also continues to evolve and will likely be an important factor in identifying women who will benefit from statin therapy for primary prevention.

Statin adverse effects. Much of the debate about statins for primary prevention stems from concern about the adverse effects of these drugs. In addition to myopathy, there have been reports of increased risks of new diabetes and cognitive impairment.¹⁶ In a post hoc analysis of the Women’s Health Initiative, the adjusted risk of diabetes was 48% higher in women taking a statin for primary prevention than in similar women not taking a statin.¹⁷ (This finding should be viewed with caution, since the data are observational.)

There has also been a question of whether women experience more side effects from statin therapy than men do. Although thin or frail women over age 80 are more susceptible to statin side effects, this finding has not been observed in younger women.¹⁸

Comment. In view of the data, it appears reasonable to consider statin therapy for primary prevention in women deemed to be at high risk based on the current guidelines. However, as always, one must consider whether the benefits outweigh the risks for the individual patient. More study is needed to better evaluate the utility of statin therapy in primary prevention.

Hormone therapy

Hormone therapy has received enormous attention in both the medical community and the public media. (Hormone therapy is either combined estrogen and progestin or estrogen alone, used to treat symptoms of menopause and to prevent osteoporosis in postmenopausal women. Here, we will discuss hormone therapy and not hormone replacement therapy, which is used specifically to treat premature menopause.)

The safety of estrogen-progestin combination therapy has been the subject of great debate since a Women’s Health Initiative study showed a trend toward a greater risk of cardiovascular disease in estrogen-progestin users.¹⁹

Women who received estrogen by itself showed no difference in cardiovascular risk compared with those who received placebo. Unopposed estrogen is rarely prescribed, since it increases the risk of endometrial cancer in women who have not undergone hysterectomy.²⁰

Both unopposed estrogen and combination therapy have also been found to increase the risk of stroke,²⁰ deep vein thrombosis, gallbladder disease, and certain forms of urinary incontinence.

Guidelines on hormone therapy. The USPSTF does not recommend hormone therapy to prevent chronic conditions, basing its decision on the findings from the Women’s Health Initiative.²¹ The American College of Cardiology and American Heart Association (ACC/AHA) 2007 guidelines advise against continuing hormone therapy in patients who present with acute coronary syndrome, although recommendations need to address a broader scope of primary and secondary prevention patients.

Does timing matter? There is a hypothesis that when hormone therapy is started may affect the cardiovascular risk. A secondary analysis of the Women’s Health Initiative study²² showed a trend towards less cardiovascular disease in women who started hormone therapy within 9 years of menopause, whereas those starting it later had a statistically significantly higher rate of cardiovascular mortality. However, all women had a higher risk of stroke while on hormone therapy, regardless of timing.²²

A study of 1,006 healthy women age 45 to 58 whose last menstrual period was 3 to 24 months before enrollment found a statistically significant reduction in the composite end point of death, hospital admission for myocardial infarction, or heart failure with hormone therapy.²³ There was no significant increase in breast cancer, deep vein thrombosis, or stroke after 10 years of randomized treatment.

A retrospective analysis of 71,237 postmenopausal women in the California Teachers Study also found a significant reduction in the rate of cardiovascular disease-related deaths with hormone therapy in younger women (ie, younger than age 65), but not in older women.²⁴ The authors concluded that it may not just be the years after menopause but also the baseline age of the woman that may influence outcomes.

In view of these studies, there is increasing recognition that hormone therapy may, in fact, still be beneficial in terms of cardiovascular and all-cause mortality in carefully selected patients. The cardiovascular risk in women, specifically older women who have had a longer duration of menopause, should also be weighed against the potential benefits of therapy in terms of quality of life and symptom relief.

Trials under way include the Kronos Early Estrogen Prevention (KEEP) and Danish Osteoporosis Prevention (DOPS) studies. KEEP is a 4-year, double-blind, randomized controlled trial of hormone therapy in women within 3 years of menopause. DOPS is an open-label trial that includes more than 1,000 women with early menopause. The results of these trials will likely affect future recommendations.

WOMEN’S SYMPTOMS: TYPICAL OR ATYPICAL?

Whether the presenting symptoms of acute coronary syndromes differ between men and women has been much debated.

More women than men seem to present with atypical symptoms.^25–27 (The term “atypical” refers to symptoms that do not include the three classic components of angina: substernal chest pain or discomfort, provoked by exertion or emotional stress, and relieved by rest or nitroglycerin, or both.²⁸)

However, most women still present with chest pain. In a study by Dey et al,²⁶ 92% of the 7,638 women with presumed acute coronary syndrome presented with chest pain. In women who had atypical symptoms, dyspnea, nausea, vomiting, and diaphoresis were the most common symptoms. Women were significantly more likely than men to present with nausea and vomiting (32% vs 23%, P = .001).

Women in the study were also more likely to have angiographically normal coronary arteries (12% vs 6%, P < .001).²⁶ This difference may be largely due to noncardiac chest pain, but it may also represent conditions such as vasospasm, microvascular disease, or stress cardiomyopathy, all of which disproportionately affect women.

An earlier review of 10 major studies found a higher percentage of women presenting with atypical symptoms (37.5% of women vs 27.4% of men).²⁵ However, symptoms were not a focus of these studies, and the findings may therefore be skewed by inaccurate documentation.

Atypical warning signs. Although most women with acute coronary syndrome present acutely with chest pain, women may have different warning signs than men. Only about one-third of women experience angina before presentation.²⁹ Compared with men, women are more likely to complain of shortness of breath, fatigue, and weakness leading up to a diagnosis of a myocardial infarction.²⁹ Therefore, the prodromal symptoms of cardiovascular disease may in fact be significantly more atypical in women than in men, suggesting the need for heightened vigilance in the cardiovascular evaluation of women who have nonanginal symptoms.

THE ROLE OF STRESS TESTING IN WOMEN

Stress testing in various forms continues to be widely used in the diagnosis of heart disease in women, although data are scarce regarding its utility in women.

The ACC/AHA guidelines continue to recommend exercise stress electrocardiography (ECG) for women who have symptoms, are at intermediate risk, and have a normal result on resting ECG.³⁰

Exercise ECG has a higher false-positive rate in women than in men,³¹ and there appears to be no relationship between exercise-induced ST-segment depression and the rate of cardiovascular mortality or all-cause mortality in women.^32,33 On the other hand, exercise ECG yields valuable additional information such as exercise capacity, chronotropic response, heart-rate recovery, and blood pressure response, all of which have important diagnostic and prognostic implications in women.³⁴

For those who have an abnormal resting ECG, the addition of an imaging test, ie, echocardiography or single-photon emission computed tomography (SPECT), is indicated. Both have limitations: SPECT can give false-positive results because of breast attenuation, and echocardiography varies in accuracy depending on the quality of acoustic windows obtained. Both exercise stress SPECT and exercise stress ECG have higher sensitivity and specificity than electrocardiographic exercise stress testing alone,³⁴ and there is evidence that the two imaging tests are comparable in women.³⁵

In those women who have baseline left bundle branch block or who cannot exercise, a pharmacologic stress test should be performed. Of course, this is a less desirable testing method, given the loss of valuable information obtained from exercising the patient.

UNDERLYING CONDITIONS THAT DISPROPORTIONATELY AFFECT WOMEN

Microvascular angina

Perimenopausal and postmenopausal women account for 70% of patients presenting with chest pain and elevated cardiac enzymes but no significant angiographic evidence of coronary artery disease.³⁶ This condition, commonly called syndrome X, is often characterized by lingering, dull chest pain after exertion and is seen more frequently in women younger than those presenting with classic cardiovascular disease.

Because at least some of these patients show evidence of ST-segment depression and reversible perfusion defects on imaging, the condition is thought to be caused by ischemia of the microvascular bed leading to microvascular angina.³⁷

Although this is still an area of research, microvascular dysfunction has recently been proposed as an explanation for these findings. Abnormal vasoconstriction and impaired vasodilation of the microvascular bed, insulin resistance, increased systemic inflammation, and abnormal pain response have all been cited as potentially contributing to microvascular dysfunction.³⁶

Estrogen deficiency is thought to play a central role in the significantly increased burden of microvascular dysfunction seen in women, with some studies suggesting that hormone therapy can relieve symptoms. However, given the concerns about adverse cardiovascular outcomes in women on hormone therapy, there has been little investigation of this treatment for this disorder.

Studies have shown worse cardiovascular outcomes and higher rates of angina-related hospitalization and repeat heart catheterizations in women with microvascular dysfunction.³⁸

Diagnosing microvascular angina must be done indirectly, as there is no safe and minimally invasive technique by which to directly observe the microvasculature. Current coronary angiographic techniques cannot image vessels smaller than 0.5 mm in diameter, and endomyocardial biopsy cannot access the larger periarterioles thought to play a major role in regulating coronary blood flow.³⁹

Image courtesy of Dr. Deborah Kwon

Because the coronary microvasculature controls total coronary resistance and therefore regulates myocardial blood flow, measuring myocardial blood flow at maximum vasodilation, termed coronary flow reserve, can indirectly evaluate the degree of microvascular dysfunction.⁴⁰ In the absence of obstructive epicardial coronary disease, noninvasive imaging techniques or provocative testing in the coronary catheterization lab can be used for this purpose. In terms of noninvasive imaging, perfusion magnetic resonance imaging (Figure 2) or positron emission tomography is often performed.⁴⁰

Coronary flow reserve can also be measured by invasive means in the catheterization laboratory after maximum hyperemia is induced by adenosine or other such vasodilatory agents.⁴¹ However, measurements obtained in this invasive manner are greatly affected by hemodynamic changes and can have poor reproducibility.⁴⁰

Proposed therapy for microvascular angina. Once a diagnosis has been made, lifestyle modification, antianginal agents, angiotensin-converting enzyme inhibitors, and statins have been suggested for therapy.³⁹ Pain management techniques are also used, given the increased pain sensitivity observed in women with this condition. However, no therapy to date has proven overwhelmingly effective in these patients, and a disproportionate number of women suffer from chronic symptoms despite these treatments. Currently, researchers are looking for new agents to treat microvascular disease.

Stress cardiomyopathy

Images courtesy of Dr. Michael Faulx and Dr. Shikhar Agarwal

Stress cardiomyopathy, also called takotsubo cardiomyopathy or “broken heart syndrome,” is another condition that disproportionately affects postmenopausal women. It is often associated with sudden emotional or physical stress. Patients present with signs and symptoms of myocardial infarction without demonstrable epicardial coronary artery disease. The hallmark of stress cardiomyopathy is left ventricular dysfunction, often severe, with classic apical ballooning that resembles a Japanese fishing pot (takotsubo) used to trap octopuses, hence the name (Figure 3).

According to a review by Akashi et al⁴² based on previously reported Mayo Clinic criteria, the diagnosis of stress cardiomyopathy includes each of the following:

• Transient hypokinesis, akinesis, or dyskinesis in the left ventricular midsegments with or without apical involvement; regional wall-motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful trigger
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture
• New abnormality on ECG (eg, ST-segment elevation, T-wave inversion) or modest elevation in cardiac troponin
• Absence of pheochromocytoma or myocarditis.

From 80% to 100% of reported cases are in women, with an average age range of 61 to 76.⁴² It is unclear why there is such an overwhelming postmenopausal female preponderance of the disease. Studies have implicated estrogen deficiency, as it appears to attenuate the levels of cardioprotective substances in the body that in part regulate catecholamine surges and may also increase the level of oxidative stress.⁴²

Several mechanisms for this condition have been proposed. The condition may be caused by multivessel epicardial coronary spasm or spontaneously resolved plaque rupture, resulting in stunned myocardium. However, the regional distribution of wall-motion abnormality is often out of proportion to the level of cardiac enzyme elevation, and in the case of plaque rupture, is frequently not consistent with a single coronary vessel.⁴² A catecholamine surge causing myocardial and neurogenic stunning has also been proposed, although many of these patients have normal catecholamine levels.⁴² Finally, microvascular dysfunction has been found in a number of patients with this condition. However, it is difficult to establish a causal relationship, since apical ballooning could result in microvascular dysfunction.⁴²

Treatment of stress cardiomyopathy has not been standardized, in part because the left ventricular dysfunction often resolves spontaneously within several weeks.^43,44 Given the proposed catecholaminergic mechanism, some experts believe that beta-blockers are contraindicated because of the resulting unopposed activation of alpha-adrenoreceptors. However, this continues to be a matter of debate. There is also no clear indication for other standard therapies for acute coronary syndrome such as aspirin and heparin, and their use appears to vary in clinical practice.

Although most patients improve with time and recurrence is exceedingly rare, it should be emphasized that they may present acutely with severe hemodynamic instability and cardiogenic shock. Therefore, advanced means of support, such as an intra-aortic balloon pump, may be indicated until the patient recovers from the acute phase of the disease.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome resulting from dissection of the coronary intimal or medial layer and associated hematoma formation, leading to coronary occlusion.^45,46 In a case series of 87 patients, 49% presented with an ST-segment elevation myocardial infarction, and 23% were found to have multivessel SCAD.⁴⁶

SCAD occurs predominantly in young, healthy women (mean age 30–45 years). Approximately 70% of cases are in women, 30% of whom are in the peripartum period.⁴⁵ The reasons for the increased risk during pregnancy have not yet been elucidated, but changing sex hormones, increased cardiac output and shear stress, and an increased inflammatory response have been implicated.⁴⁵

Diagnosing SCAD. Coronary angiography should be performed with extreme caution in patients suspected of having SCAD, given the risk of further dissection of the artery with forceful injections. In certain cases, it may be difficult to detect SCAD on routine angiography if there is no communication between the true and false lumen.

If the suspicion for SCAD is high, intravascular ultrasonography or optical coherence tomography can be used to better evaluate the vessel.⁴⁵ Although optical coherence tomography has greater spatial resolution, it is more costly and is not as widely used as intravascular ultrasonography in the clinical setting

Managing SCAD. Although conservative management and coronary artery bypass grafting have been shown to cause minimal in-hospital morbidity, percutaneous coronary intervention has been complicated by technical failure in up to 35% of patients in one series.⁴⁶

While there is no standardized way to manage these patients, experts currently recommend conservative management with standard therapies for acute coronary syndrome (Figure 4). Although antithrombotic agents can decrease thrombus burden, they must be used with caution, because they also increase the risk of bleeding into the false lumen.

If patients experience recurrent or ongoing ischemia despite conservative management, then revascularization should be considered. Optical coherence tomography or intravascular ultrasonography is recommended to ensure proper stent alignment and positioning.

Coronary artery bypass grafting could be considered in preference to percutaneous coronary intervention, given that the former appears to be safer,⁴⁶ although this requires further investigation. Some studies have cautioned against using fibrinolytic therapy, based on anecdotal evidence that it may further propagate the dissection,⁴⁵ although this therapy has been used in other case studies.⁴⁶

While mortality rates are relatively low (95% survival at 2 years),⁴⁵ the estimated risk of recurrent SCAD at 10 years is approximately 30%.⁴⁶

Image courtesy of Dr. Heather Gornik

Associated with fibromuscular dysplasia. Of note, a sizeable number of patients with SCAD have been found to have fibromuscular dysplasia. This is a nonatherosclerotic, noninflammatory vascular condition that can affect any vascular bed in the body, although there is a predilection for the renal and carotid arteries (Figure 5).⁴⁷ Fibromuscular dysplasia also disproportionately affects women and appears to be a concomitant condition in the majority of patients with SCAD.⁴⁷ Imaging of the carotid and renal arteries of patients with SCAD has revealed a number of cases of fibromuscular dysplasia.^46,48 This noted association will likely allow for ongoing research to better understand the pathophysiology of these two conditions.

Although long considered a disease of elderly men, cardiovascular disease is increasingly recognized for its impact on women. In fact, it is now the leading cause of death in women worldwide, and in the United States more women than men die of it.¹

Given this epidemic of cardiovascular disease in women, more research is now being dedicated to identifying sex-specific aspects of cardiovascular disease, the better to prevent and treat it.

This review will focus on the most recent information about how prevention, symptoms, and underlying cardiovascular conditions differ in women.

PRIMARY PREVENTION: ONGOING DEBATE

Women who diet, exercise, and abstain from smoking have an 80% lower rate of cardiovascular events than the female population overall.² However, beyond lifestyle modification and blood pressure control, there is ongoing debate as to the efficacy of our available therapies for preventing cardiovascular disease in women.

Aspirin for primary prevention in women: No benefit?

The use of aspirin to prevent cardiovascular disease in women has long been controversial. Several trials showed a lower rate of myocardial infarction in people using aspirin for primary prevention, but most of the patients in the initial trials were men (Table 1).³

The Women’s Health Study⁴ assigned 39,876 women age 45 and older to receive either aspirin (100 mg on alternate days) or placebo, and monitored them for more than 10 years for major cardiovascular events (non-fatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes).

The results, published in 2005, showed that the rates of myocardial infarction and cardiovascular death were not significantly lower in the aspirin group, although the rate of ischemic stroke was 24% lower. There were more hemorrhagic strokes in the aspirin group (not statistically significant), and there was significantly more gastrointestinal bleeding. The study showed the relative risk (RR) and 95% confidence interval (CI) for several outcomes in aspirin users were:

• Myocardial infarction—RR 1.02, 95% CI 0.84–1.25, P = .83
• Cardiovascular death—RR 0.95, 95% CI 0.74–1.22, P = .68
• Ischemic stroke—RR 0.76, 95% CI 0.63–0.93, P = .009
• Hemorrhagic stroke—RR 1.24, 95% CI 0.82–1.87, P = .31
• Gastrointestinal bleeding—RR 1.4, 95% CI 1.07–1.83, P = .02.

A later analysis indicated that noncompliance had no effect on these results.⁵

However, a subgroup analysis of women over age 65 found a significant reduction in the rate of myocardial infarction and in the composite end point of myocardial infarction, stroke, and cardiovascular death, although there was a trend toward a higher rate of gastrointestinal bleeding. The numbers in aspirin users in the subgroup over age 65 were as follows:

• Myocardial infarction—RR 0.66, 95% CI 0.44–0.97, P = .04
• Composite end point—RR 0.74, 95% CI 0.59–0.92, P = .008.

Aspirin was taken every other day and at a higher dose than the 81 mg recommended in the United States, although it is unclear how these differences may have affected the results.

United States Preventive Services Task Force (USPSTF) recommendations. Although the USPSTF currently recommends aspirin for men age 45 to 79 to prevent myocardial infarction, it offers no such recommendation for women, largely because of the results of the Women’s Health Initiative study. However, it does recommend aspirin to prevent ischemic stroke in women age 55 to 79.³ Additionally, aspirin can be considered for prevention of myocardial infarction in women who are over age 65 or at high risk.⁶

This is based on Women’s Health Study data for women over age 65 showing a number needed to treat of 47 to prevent 1 cardiovascular event, whereas the number needed to harm, defined by a major hemorrhagic event, was 128. In contrast, in women younger than age 65, the number needed to treat was 2,001 and the number needed to harm was 196.⁴

High-risk features, as defined by the guidelines, are a history of coronary artery disease, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes, or chronic kidney disease, or a 10-year predicted risk of cardiovascular disease of more than 10%.

Jardine et al⁷ reported that aspirin was beneficial in patients with chronic kidney disease. The rates of cardiovascular death, death from any cause, and stroke were significantly lower in patients with a glomerular filtration rate (GFR) less than 45 mL/min if they received aspirin. The rates were also lower in aspirin recipients with a GFR between 46 and 60 mL/min, but the difference was not statistically significant.

Comments. Given the risk of significant gastrointestinal bleeding and a trend toward hemorrhagic stroke with aspirin use,⁴ it is important to weigh the risks and benefits of aspirin for primary prevention in women.

Our understanding of the reasons for sex differences in the clinical benefits of aspirin for primary prevention is limited at this point. Studies have shown a higher prevalence of platelet reactivity and aspirin resistance in women than in men, suggesting that hormonal differences may play a role.⁸ There has been mention of using higher doses of aspirin in women to achieve the same level of platelet inhibition as in men. However, studies have shown essentially equal platelet inhibition in both men and women after aspirin administration.⁹ Therefore, more work needs to be done to better understand the observed sex differences in response to aspirin.

Given suggestions that statins may not be effective in women¹⁰ and the fact that women were underrepresented in earlier statin trials, a number of studies have examined this issue in the last several years.

The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin)¹⁰ enrolled patients who had no history of coronary artery disease and who had a C-reactive protein level equal to or greater than 2 mg/L and a low-density lipoprotein cholesterol level of less than 130 mg/dL. (Of note, these patients would not have met the criteria for receiving a statin for primary prevention according to the current Adult Treatment Panel guidelines.)

The women in the trial who received rosuvastatin had a 46% lower incidence of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes. In addition, a meta-analysis performed by the authors showed a one-third reduction of cardiovascular disease end points in women. However, there was no reduction in the mortality rate.

Reprinted from Kostis WJ, et al. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59:572–582, with permission from Elsevier.

Other statin trials. A later meta-analysis of randomized primary prevention trials found that men and women derived similar benefit from statins in terms of cardiovascular disease end points and all-cause mortality (Figure 1),¹¹ although five of the trials included a small number of secondary prevention patients. In contrast, a meta-analysis of only primary prevention patients showed no benefit of statin therapy in all-cause mortality, although the authors acknowledged that there were insufficient data to look specifically at women in this sample.¹²

A Cochrane review conducted before the JUPITER data were available concluded that there was insufficient evidence to prescribe statins for primary prevention in patients at low cardiovascular risk.13 However, an updated version that included results of the JUPITER trial concluded that there was a reduction in the rate of all-cause mortality and cardiovascular events in both men and women receiving a statin for primary prevention.14

Given these conflicting results, debate continues as to the benefit of statins for primary prevention, not only in women but in the population as a whole.^15,16 The definition of high risk, in terms of comorbidities and lipid profile, also continues to evolve and will likely be an important factor in identifying women who will benefit from statin therapy for primary prevention.

Statin adverse effects. Much of the debate about statins for primary prevention stems from concern about the adverse effects of these drugs. In addition to myopathy, there have been reports of increased risks of new diabetes and cognitive impairment.¹⁶ In a post hoc analysis of the Women’s Health Initiative, the adjusted risk of diabetes was 48% higher in women taking a statin for primary prevention than in similar women not taking a statin.¹⁷ (This finding should be viewed with caution, since the data are observational.)

There has also been a question of whether women experience more side effects from statin therapy than men do. Although thin or frail women over age 80 are more susceptible to statin side effects, this finding has not been observed in younger women.¹⁸

Comment. In view of the data, it appears reasonable to consider statin therapy for primary prevention in women deemed to be at high risk based on the current guidelines. However, as always, one must consider whether the benefits outweigh the risks for the individual patient. More study is needed to better evaluate the utility of statin therapy in primary prevention.

Hormone therapy

Hormone therapy has received enormous attention in both the medical community and the public media. (Hormone therapy is either combined estrogen and progestin or estrogen alone, used to treat symptoms of menopause and to prevent osteoporosis in postmenopausal women. Here, we will discuss hormone therapy and not hormone replacement therapy, which is used specifically to treat premature menopause.)

The safety of estrogen-progestin combination therapy has been the subject of great debate since a Women’s Health Initiative study showed a trend toward a greater risk of cardiovascular disease in estrogen-progestin users.¹⁹

Women who received estrogen by itself showed no difference in cardiovascular risk compared with those who received placebo. Unopposed estrogen is rarely prescribed, since it increases the risk of endometrial cancer in women who have not undergone hysterectomy.²⁰

Both unopposed estrogen and combination therapy have also been found to increase the risk of stroke,²⁰ deep vein thrombosis, gallbladder disease, and certain forms of urinary incontinence.

Guidelines on hormone therapy. The USPSTF does not recommend hormone therapy to prevent chronic conditions, basing its decision on the findings from the Women’s Health Initiative.²¹ The American College of Cardiology and American Heart Association (ACC/AHA) 2007 guidelines advise against continuing hormone therapy in patients who present with acute coronary syndrome, although recommendations need to address a broader scope of primary and secondary prevention patients.

Does timing matter? There is a hypothesis that when hormone therapy is started may affect the cardiovascular risk. A secondary analysis of the Women’s Health Initiative study²² showed a trend towards less cardiovascular disease in women who started hormone therapy within 9 years of menopause, whereas those starting it later had a statistically significantly higher rate of cardiovascular mortality. However, all women had a higher risk of stroke while on hormone therapy, regardless of timing.²²

A study of 1,006 healthy women age 45 to 58 whose last menstrual period was 3 to 24 months before enrollment found a statistically significant reduction in the composite end point of death, hospital admission for myocardial infarction, or heart failure with hormone therapy.²³ There was no significant increase in breast cancer, deep vein thrombosis, or stroke after 10 years of randomized treatment.

A retrospective analysis of 71,237 postmenopausal women in the California Teachers Study also found a significant reduction in the rate of cardiovascular disease-related deaths with hormone therapy in younger women (ie, younger than age 65), but not in older women.²⁴ The authors concluded that it may not just be the years after menopause but also the baseline age of the woman that may influence outcomes.

In view of these studies, there is increasing recognition that hormone therapy may, in fact, still be beneficial in terms of cardiovascular and all-cause mortality in carefully selected patients. The cardiovascular risk in women, specifically older women who have had a longer duration of menopause, should also be weighed against the potential benefits of therapy in terms of quality of life and symptom relief.

Trials under way include the Kronos Early Estrogen Prevention (KEEP) and Danish Osteoporosis Prevention (DOPS) studies. KEEP is a 4-year, double-blind, randomized controlled trial of hormone therapy in women within 3 years of menopause. DOPS is an open-label trial that includes more than 1,000 women with early menopause. The results of these trials will likely affect future recommendations.

WOMEN’S SYMPTOMS: TYPICAL OR ATYPICAL?

Whether the presenting symptoms of acute coronary syndromes differ between men and women has been much debated.

More women than men seem to present with atypical symptoms.^25–27 (The term “atypical” refers to symptoms that do not include the three classic components of angina: substernal chest pain or discomfort, provoked by exertion or emotional stress, and relieved by rest or nitroglycerin, or both.²⁸)

However, most women still present with chest pain. In a study by Dey et al,²⁶ 92% of the 7,638 women with presumed acute coronary syndrome presented with chest pain. In women who had atypical symptoms, dyspnea, nausea, vomiting, and diaphoresis were the most common symptoms. Women were significantly more likely than men to present with nausea and vomiting (32% vs 23%, P = .001).

Women in the study were also more likely to have angiographically normal coronary arteries (12% vs 6%, P < .001).²⁶ This difference may be largely due to noncardiac chest pain, but it may also represent conditions such as vasospasm, microvascular disease, or stress cardiomyopathy, all of which disproportionately affect women.

An earlier review of 10 major studies found a higher percentage of women presenting with atypical symptoms (37.5% of women vs 27.4% of men).²⁵ However, symptoms were not a focus of these studies, and the findings may therefore be skewed by inaccurate documentation.

Atypical warning signs. Although most women with acute coronary syndrome present acutely with chest pain, women may have different warning signs than men. Only about one-third of women experience angina before presentation.²⁹ Compared with men, women are more likely to complain of shortness of breath, fatigue, and weakness leading up to a diagnosis of a myocardial infarction.²⁹ Therefore, the prodromal symptoms of cardiovascular disease may in fact be significantly more atypical in women than in men, suggesting the need for heightened vigilance in the cardiovascular evaluation of women who have nonanginal symptoms.

THE ROLE OF STRESS TESTING IN WOMEN

Stress testing in various forms continues to be widely used in the diagnosis of heart disease in women, although data are scarce regarding its utility in women.

The ACC/AHA guidelines continue to recommend exercise stress electrocardiography (ECG) for women who have symptoms, are at intermediate risk, and have a normal result on resting ECG.³⁰

Exercise ECG has a higher false-positive rate in women than in men,³¹ and there appears to be no relationship between exercise-induced ST-segment depression and the rate of cardiovascular mortality or all-cause mortality in women.^32,33 On the other hand, exercise ECG yields valuable additional information such as exercise capacity, chronotropic response, heart-rate recovery, and blood pressure response, all of which have important diagnostic and prognostic implications in women.³⁴

For those who have an abnormal resting ECG, the addition of an imaging test, ie, echocardiography or single-photon emission computed tomography (SPECT), is indicated. Both have limitations: SPECT can give false-positive results because of breast attenuation, and echocardiography varies in accuracy depending on the quality of acoustic windows obtained. Both exercise stress SPECT and exercise stress ECG have higher sensitivity and specificity than electrocardiographic exercise stress testing alone,³⁴ and there is evidence that the two imaging tests are comparable in women.³⁵

In those women who have baseline left bundle branch block or who cannot exercise, a pharmacologic stress test should be performed. Of course, this is a less desirable testing method, given the loss of valuable information obtained from exercising the patient.

UNDERLYING CONDITIONS THAT DISPROPORTIONATELY AFFECT WOMEN

Microvascular angina

Perimenopausal and postmenopausal women account for 70% of patients presenting with chest pain and elevated cardiac enzymes but no significant angiographic evidence of coronary artery disease.³⁶ This condition, commonly called syndrome X, is often characterized by lingering, dull chest pain after exertion and is seen more frequently in women younger than those presenting with classic cardiovascular disease.

Because at least some of these patients show evidence of ST-segment depression and reversible perfusion defects on imaging, the condition is thought to be caused by ischemia of the microvascular bed leading to microvascular angina.³⁷

Although this is still an area of research, microvascular dysfunction has recently been proposed as an explanation for these findings. Abnormal vasoconstriction and impaired vasodilation of the microvascular bed, insulin resistance, increased systemic inflammation, and abnormal pain response have all been cited as potentially contributing to microvascular dysfunction.³⁶

Estrogen deficiency is thought to play a central role in the significantly increased burden of microvascular dysfunction seen in women, with some studies suggesting that hormone therapy can relieve symptoms. However, given the concerns about adverse cardiovascular outcomes in women on hormone therapy, there has been little investigation of this treatment for this disorder.

Studies have shown worse cardiovascular outcomes and higher rates of angina-related hospitalization and repeat heart catheterizations in women with microvascular dysfunction.³⁸

Diagnosing microvascular angina must be done indirectly, as there is no safe and minimally invasive technique by which to directly observe the microvasculature. Current coronary angiographic techniques cannot image vessels smaller than 0.5 mm in diameter, and endomyocardial biopsy cannot access the larger periarterioles thought to play a major role in regulating coronary blood flow.³⁹

Image courtesy of Dr. Deborah Kwon

Because the coronary microvasculature controls total coronary resistance and therefore regulates myocardial blood flow, measuring myocardial blood flow at maximum vasodilation, termed coronary flow reserve, can indirectly evaluate the degree of microvascular dysfunction.⁴⁰ In the absence of obstructive epicardial coronary disease, noninvasive imaging techniques or provocative testing in the coronary catheterization lab can be used for this purpose. In terms of noninvasive imaging, perfusion magnetic resonance imaging (Figure 2) or positron emission tomography is often performed.⁴⁰

Coronary flow reserve can also be measured by invasive means in the catheterization laboratory after maximum hyperemia is induced by adenosine or other such vasodilatory agents.⁴¹ However, measurements obtained in this invasive manner are greatly affected by hemodynamic changes and can have poor reproducibility.⁴⁰

Proposed therapy for microvascular angina. Once a diagnosis has been made, lifestyle modification, antianginal agents, angiotensin-converting enzyme inhibitors, and statins have been suggested for therapy.³⁹ Pain management techniques are also used, given the increased pain sensitivity observed in women with this condition. However, no therapy to date has proven overwhelmingly effective in these patients, and a disproportionate number of women suffer from chronic symptoms despite these treatments. Currently, researchers are looking for new agents to treat microvascular disease.

Stress cardiomyopathy

Images courtesy of Dr. Michael Faulx and Dr. Shikhar Agarwal

Stress cardiomyopathy, also called takotsubo cardiomyopathy or “broken heart syndrome,” is another condition that disproportionately affects postmenopausal women. It is often associated with sudden emotional or physical stress. Patients present with signs and symptoms of myocardial infarction without demonstrable epicardial coronary artery disease. The hallmark of stress cardiomyopathy is left ventricular dysfunction, often severe, with classic apical ballooning that resembles a Japanese fishing pot (takotsubo) used to trap octopuses, hence the name (Figure 3).

According to a review by Akashi et al⁴² based on previously reported Mayo Clinic criteria, the diagnosis of stress cardiomyopathy includes each of the following:

• Transient hypokinesis, akinesis, or dyskinesis in the left ventricular midsegments with or without apical involvement; regional wall-motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful trigger
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture
• New abnormality on ECG (eg, ST-segment elevation, T-wave inversion) or modest elevation in cardiac troponin
• Absence of pheochromocytoma or myocarditis.

From 80% to 100% of reported cases are in women, with an average age range of 61 to 76.⁴² It is unclear why there is such an overwhelming postmenopausal female preponderance of the disease. Studies have implicated estrogen deficiency, as it appears to attenuate the levels of cardioprotective substances in the body that in part regulate catecholamine surges and may also increase the level of oxidative stress.⁴²

Several mechanisms for this condition have been proposed. The condition may be caused by multivessel epicardial coronary spasm or spontaneously resolved plaque rupture, resulting in stunned myocardium. However, the regional distribution of wall-motion abnormality is often out of proportion to the level of cardiac enzyme elevation, and in the case of plaque rupture, is frequently not consistent with a single coronary vessel.⁴² A catecholamine surge causing myocardial and neurogenic stunning has also been proposed, although many of these patients have normal catecholamine levels.⁴² Finally, microvascular dysfunction has been found in a number of patients with this condition. However, it is difficult to establish a causal relationship, since apical ballooning could result in microvascular dysfunction.⁴²

Treatment of stress cardiomyopathy has not been standardized, in part because the left ventricular dysfunction often resolves spontaneously within several weeks.^43,44 Given the proposed catecholaminergic mechanism, some experts believe that beta-blockers are contraindicated because of the resulting unopposed activation of alpha-adrenoreceptors. However, this continues to be a matter of debate. There is also no clear indication for other standard therapies for acute coronary syndrome such as aspirin and heparin, and their use appears to vary in clinical practice.

Although most patients improve with time and recurrence is exceedingly rare, it should be emphasized that they may present acutely with severe hemodynamic instability and cardiogenic shock. Therefore, advanced means of support, such as an intra-aortic balloon pump, may be indicated until the patient recovers from the acute phase of the disease.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome resulting from dissection of the coronary intimal or medial layer and associated hematoma formation, leading to coronary occlusion.^45,46 In a case series of 87 patients, 49% presented with an ST-segment elevation myocardial infarction, and 23% were found to have multivessel SCAD.⁴⁶

SCAD occurs predominantly in young, healthy women (mean age 30–45 years). Approximately 70% of cases are in women, 30% of whom are in the peripartum period.⁴⁵ The reasons for the increased risk during pregnancy have not yet been elucidated, but changing sex hormones, increased cardiac output and shear stress, and an increased inflammatory response have been implicated.⁴⁵

Diagnosing SCAD. Coronary angiography should be performed with extreme caution in patients suspected of having SCAD, given the risk of further dissection of the artery with forceful injections. In certain cases, it may be difficult to detect SCAD on routine angiography if there is no communication between the true and false lumen.

If the suspicion for SCAD is high, intravascular ultrasonography or optical coherence tomography can be used to better evaluate the vessel.⁴⁵ Although optical coherence tomography has greater spatial resolution, it is more costly and is not as widely used as intravascular ultrasonography in the clinical setting

Managing SCAD. Although conservative management and coronary artery bypass grafting have been shown to cause minimal in-hospital morbidity, percutaneous coronary intervention has been complicated by technical failure in up to 35% of patients in one series.⁴⁶

While there is no standardized way to manage these patients, experts currently recommend conservative management with standard therapies for acute coronary syndrome (Figure 4). Although antithrombotic agents can decrease thrombus burden, they must be used with caution, because they also increase the risk of bleeding into the false lumen.

If patients experience recurrent or ongoing ischemia despite conservative management, then revascularization should be considered. Optical coherence tomography or intravascular ultrasonography is recommended to ensure proper stent alignment and positioning.

Coronary artery bypass grafting could be considered in preference to percutaneous coronary intervention, given that the former appears to be safer,⁴⁶ although this requires further investigation. Some studies have cautioned against using fibrinolytic therapy, based on anecdotal evidence that it may further propagate the dissection,⁴⁵ although this therapy has been used in other case studies.⁴⁶

While mortality rates are relatively low (95% survival at 2 years),⁴⁵ the estimated risk of recurrent SCAD at 10 years is approximately 30%.⁴⁶

Image courtesy of Dr. Heather Gornik

Associated with fibromuscular dysplasia. Of note, a sizeable number of patients with SCAD have been found to have fibromuscular dysplasia. This is a nonatherosclerotic, noninflammatory vascular condition that can affect any vascular bed in the body, although there is a predilection for the renal and carotid arteries (Figure 5).⁴⁷ Fibromuscular dysplasia also disproportionately affects women and appears to be a concomitant condition in the majority of patients with SCAD.⁴⁷ Imaging of the carotid and renal arteries of patients with SCAD has revealed a number of cases of fibromuscular dysplasia.^46,48 This noted association will likely allow for ongoing research to better understand the pathophysiology of these two conditions.

A 35-year-old man presented to the emergency department because of night sweats, fever, chills, and shortness of breath. He also had an acute onset of blue discoloration of his right fourth finger. His symptoms (except for the finger discoloration) had begun about 6 months previously and had rapidly progressed despite several courses of different antibiotics of different types, given both intravenously in the hospital and orally at home. He had lost 20 lb during this time. Previously, he had been healthy.

About 1 month after his symptoms began, he had consulted his primary care physician, who detected a new grade 4/6 systolic and diastolic murmur. Transthoracic echocardiography about 2 months after that demonstrated mild aortic and mitral insufficiency but no echocardiographic features supporting infective endocarditis. Of note, the patient had no risk factors for endocarditis such as illicit drug use or poor dental health.

In the emergency department, his temperature was 99.4°F (37.4°C), pulse 109 beats per minute, and blood pressure 126/60 mm Hg. He had a grade 3/6 harsh holosystolic murmur best heard at the right upper sternal border, a grade 3/4 holodiastolic murmur audible across the precordium, and a grade 3/4 holosystolic blowing murmur best heard at the cardiac apex. Other findings included signs of aortic insufficiency—the Duroziez sign (a diastolic murmur heard over the femoral artery when compressed), Watson’s water-hammer pulse (indicating a wide pulse pressure), and the Müller sign (pulsation of the uvula)—and small Janeway lesions on the inner aspect of his right arm and palm.

Electrocardiography showed normal sinus rhythm, PR interval 128 ms, QRS complex 100 ms, QT interval 360 ms, and corrected QT interval 473 ms.

Blood cultures grew Streptococcus sanguinis. Both transthoracic and transesophageal echocardiography were done promptly and revealed multiple mobile echodensities attached to a trileaflet aortic valve, consistent with vegetations and valve leaflet destruction; severe (4+) aortic regurgitation with flow reversal in the abdominal aorta; mild mitral regurgitation; and a mitral valve aneurysm with mild mitral regurgitation (Figure 1).

INFECTIVE ENDOCARDITIS: WORTH CONSIDERING

S sanguinis is a member of the group of viridans streptococci. As a normal inhabitant of the healthy human mouth, it is found in dental plaque. It may enter the bloodstream during dental cleaning and may colonize the heart valves, particularly the mitral and aortic valves, where it is the most common cause of subacute bacterial endocarditis.

Infective endocarditis is often diagnosed clinically with the Duke criteria (www.med-calc.com/endocarditis.html).¹ However, the variability of the clinical presentation and the nonspecific nature of the initial workup often create a diagnostic challenge for the evaluating physician.^1,2

In cases of recurrent persistent fever and a new heart murmur, infective endocarditis must always be considered. Blood cultures should be ordered early and repeatedly. If blood cultures are positive, transesophageal echocardiography should be done without delay if transthoracic echocardiography was unremarkable. Prompt diagnosis and surgical intervention prevent complications.

MITRAL VALVE ANEURYSM IN AORTIC VALVE ENDOCARDITIS

Aortic valve endocarditis often also involves the mitral valve; mitral valve endocarditis is seen in 17% of patients undergoing surgery for aortic valve endocarditis.³ Proposed mechanisms for this association include jet lesions from aortic regurgitation, vegetation prolapse with direct contact between the aortic valve and anterior mitral leaflet (“kissing lesions”), and direct local spread of infection.^4–7

One of every five patients with mitral valve involvement in aortic valve endocarditis has a mitral valve aneurysm.³ This is a serious finding, as it can lead to septic embolization. Also, the weakened lining of the mitral valve aneurysm can rupture, resulting in severe mitral regurgitation, acute pulmonary edema, and precipitous cardiopulmonary decompensation.⁵

Transesophageal echocardiography is more sensitive than transthoracic echocardiography for detecting mitral valve aneurysm.⁸ On two-dimensional echocardiography, the lesion appears as a narrow-necked, saccular echolucency with systolic protrusion into the left atrium. Color Doppler imaging often shows turbulent, high-velocity flow.

Differential diagnosis of mitral valve aneurysm

Differential diagnostic considerations include a valvular blood cyst, a congenital cardiac diverticulum, and mitral valve prolapse.

Valvular blood cysts are extremely rare in adults.⁹ These benign, congenital tumors are most often found on the atrioventricular valves in infants, in whom the reported incidence is between 25% and 100%. In almost all cases, these cysts are believed to regress spontaneously with time.

In almost all reported cases, the cyst involved the valvular apparatus or papillary muscle of the tricuspid, pulmonary, or mitral valve.¹⁰ Cysts consist of a benign diverticulum lined with flattened, cobblestone-shaped endothelium and are filled with blood. They can cause heart murmurs in otherwise asymptomatic patients.

On echocardiography, a blood cyst appears as an oval mass (often at the interatrial septum), often with normal cardiac function. In the rare case in which a blood cyst is found incidentally during echocardiography, the hemodynamic impact, if any, should be determined by Doppler techniques.

When benign, a valvular blood cyst can be safely monitored with echocardiographic follow-up.¹¹ Treatment involves surgical resection of the mass in symptomatic patients in whom cardiac function is impaired by the presence of the cyst.

Congenital cardiac diverticuli are extremely rare, most often seen in children, and associated with a midline thoracoabdominal defect. Echocardiography can differentiate a ventricular diverticulum from an aneurysm or a pseudoaneurysm.

A ventricular diverticulum has a fibrous, narrow neck connecting with the ventricle, and a small circular echo-free space that communicates with the ventricle via this narrow neck.² Doppler imaging shows systolic flow from the diverticulum to the ventricle, and systolic contractility may also be seen during cardiac catheterization. Congenital diverticulum is typically confused with ventricular aneurysm and, to a lesser degree, with mitral valve aneurysm.

Mitral valve prolapse is characterized by interchordal ballooning or hooding of the mitral valve leaflets that occurs when one or both floppy, enlarged leaflets prolapse into the left atrium during systole.

BACK TO OUR PATIENT

The patient underwent open heart surgery, with successful repair of the aortic root, replacement of the aortic valve, and repair of the mitral valve. An abscess was found within the aneurysmal cavity.

A 35-year-old man presented to the emergency department because of night sweats, fever, chills, and shortness of breath. He also had an acute onset of blue discoloration of his right fourth finger. His symptoms (except for the finger discoloration) had begun about 6 months previously and had rapidly progressed despite several courses of different antibiotics of different types, given both intravenously in the hospital and orally at home. He had lost 20 lb during this time. Previously, he had been healthy.

About 1 month after his symptoms began, he had consulted his primary care physician, who detected a new grade 4/6 systolic and diastolic murmur. Transthoracic echocardiography about 2 months after that demonstrated mild aortic and mitral insufficiency but no echocardiographic features supporting infective endocarditis. Of note, the patient had no risk factors for endocarditis such as illicit drug use or poor dental health.

In the emergency department, his temperature was 99.4°F (37.4°C), pulse 109 beats per minute, and blood pressure 126/60 mm Hg. He had a grade 3/6 harsh holosystolic murmur best heard at the right upper sternal border, a grade 3/4 holodiastolic murmur audible across the precordium, and a grade 3/4 holosystolic blowing murmur best heard at the cardiac apex. Other findings included signs of aortic insufficiency—the Duroziez sign (a diastolic murmur heard over the femoral artery when compressed), Watson’s water-hammer pulse (indicating a wide pulse pressure), and the Müller sign (pulsation of the uvula)—and small Janeway lesions on the inner aspect of his right arm and palm.

Electrocardiography showed normal sinus rhythm, PR interval 128 ms, QRS complex 100 ms, QT interval 360 ms, and corrected QT interval 473 ms.

Blood cultures grew Streptococcus sanguinis. Both transthoracic and transesophageal echocardiography were done promptly and revealed multiple mobile echodensities attached to a trileaflet aortic valve, consistent with vegetations and valve leaflet destruction; severe (4+) aortic regurgitation with flow reversal in the abdominal aorta; mild mitral regurgitation; and a mitral valve aneurysm with mild mitral regurgitation (Figure 1).

INFECTIVE ENDOCARDITIS: WORTH CONSIDERING

S sanguinis is a member of the group of viridans streptococci. As a normal inhabitant of the healthy human mouth, it is found in dental plaque. It may enter the bloodstream during dental cleaning and may colonize the heart valves, particularly the mitral and aortic valves, where it is the most common cause of subacute bacterial endocarditis.

Infective endocarditis is often diagnosed clinically with the Duke criteria (www.med-calc.com/endocarditis.html).¹ However, the variability of the clinical presentation and the nonspecific nature of the initial workup often create a diagnostic challenge for the evaluating physician.^1,2

In cases of recurrent persistent fever and a new heart murmur, infective endocarditis must always be considered. Blood cultures should be ordered early and repeatedly. If blood cultures are positive, transesophageal echocardiography should be done without delay if transthoracic echocardiography was unremarkable. Prompt diagnosis and surgical intervention prevent complications.

MITRAL VALVE ANEURYSM IN AORTIC VALVE ENDOCARDITIS

Aortic valve endocarditis often also involves the mitral valve; mitral valve endocarditis is seen in 17% of patients undergoing surgery for aortic valve endocarditis.³ Proposed mechanisms for this association include jet lesions from aortic regurgitation, vegetation prolapse with direct contact between the aortic valve and anterior mitral leaflet (“kissing lesions”), and direct local spread of infection.^4–7

One of every five patients with mitral valve involvement in aortic valve endocarditis has a mitral valve aneurysm.³ This is a serious finding, as it can lead to septic embolization. Also, the weakened lining of the mitral valve aneurysm can rupture, resulting in severe mitral regurgitation, acute pulmonary edema, and precipitous cardiopulmonary decompensation.⁵

Transesophageal echocardiography is more sensitive than transthoracic echocardiography for detecting mitral valve aneurysm.⁸ On two-dimensional echocardiography, the lesion appears as a narrow-necked, saccular echolucency with systolic protrusion into the left atrium. Color Doppler imaging often shows turbulent, high-velocity flow.

Differential diagnosis of mitral valve aneurysm

Differential diagnostic considerations include a valvular blood cyst, a congenital cardiac diverticulum, and mitral valve prolapse.

Valvular blood cysts are extremely rare in adults.⁹ These benign, congenital tumors are most often found on the atrioventricular valves in infants, in whom the reported incidence is between 25% and 100%. In almost all cases, these cysts are believed to regress spontaneously with time.

In almost all reported cases, the cyst involved the valvular apparatus or papillary muscle of the tricuspid, pulmonary, or mitral valve.¹⁰ Cysts consist of a benign diverticulum lined with flattened, cobblestone-shaped endothelium and are filled with blood. They can cause heart murmurs in otherwise asymptomatic patients.

On echocardiography, a blood cyst appears as an oval mass (often at the interatrial septum), often with normal cardiac function. In the rare case in which a blood cyst is found incidentally during echocardiography, the hemodynamic impact, if any, should be determined by Doppler techniques.

When benign, a valvular blood cyst can be safely monitored with echocardiographic follow-up.¹¹ Treatment involves surgical resection of the mass in symptomatic patients in whom cardiac function is impaired by the presence of the cyst.

Congenital cardiac diverticuli are extremely rare, most often seen in children, and associated with a midline thoracoabdominal defect. Echocardiography can differentiate a ventricular diverticulum from an aneurysm or a pseudoaneurysm.

A ventricular diverticulum has a fibrous, narrow neck connecting with the ventricle, and a small circular echo-free space that communicates with the ventricle via this narrow neck.² Doppler imaging shows systolic flow from the diverticulum to the ventricle, and systolic contractility may also be seen during cardiac catheterization. Congenital diverticulum is typically confused with ventricular aneurysm and, to a lesser degree, with mitral valve aneurysm.

Mitral valve prolapse is characterized by interchordal ballooning or hooding of the mitral valve leaflets that occurs when one or both floppy, enlarged leaflets prolapse into the left atrium during systole.

BACK TO OUR PATIENT

The patient underwent open heart surgery, with successful repair of the aortic root, replacement of the aortic valve, and repair of the mitral valve. An abscess was found within the aneurysmal cavity.

A 35-year-old man presented to the emergency department because of night sweats, fever, chills, and shortness of breath. He also had an acute onset of blue discoloration of his right fourth finger. His symptoms (except for the finger discoloration) had begun about 6 months previously and had rapidly progressed despite several courses of different antibiotics of different types, given both intravenously in the hospital and orally at home. He had lost 20 lb during this time. Previously, he had been healthy.

About 1 month after his symptoms began, he had consulted his primary care physician, who detected a new grade 4/6 systolic and diastolic murmur. Transthoracic echocardiography about 2 months after that demonstrated mild aortic and mitral insufficiency but no echocardiographic features supporting infective endocarditis. Of note, the patient had no risk factors for endocarditis such as illicit drug use or poor dental health.

In the emergency department, his temperature was 99.4°F (37.4°C), pulse 109 beats per minute, and blood pressure 126/60 mm Hg. He had a grade 3/6 harsh holosystolic murmur best heard at the right upper sternal border, a grade 3/4 holodiastolic murmur audible across the precordium, and a grade 3/4 holosystolic blowing murmur best heard at the cardiac apex. Other findings included signs of aortic insufficiency—the Duroziez sign (a diastolic murmur heard over the femoral artery when compressed), Watson’s water-hammer pulse (indicating a wide pulse pressure), and the Müller sign (pulsation of the uvula)—and small Janeway lesions on the inner aspect of his right arm and palm.

Electrocardiography showed normal sinus rhythm, PR interval 128 ms, QRS complex 100 ms, QT interval 360 ms, and corrected QT interval 473 ms.

Blood cultures grew Streptococcus sanguinis. Both transthoracic and transesophageal echocardiography were done promptly and revealed multiple mobile echodensities attached to a trileaflet aortic valve, consistent with vegetations and valve leaflet destruction; severe (4+) aortic regurgitation with flow reversal in the abdominal aorta; mild mitral regurgitation; and a mitral valve aneurysm with mild mitral regurgitation (Figure 1).

INFECTIVE ENDOCARDITIS: WORTH CONSIDERING

S sanguinis is a member of the group of viridans streptococci. As a normal inhabitant of the healthy human mouth, it is found in dental plaque. It may enter the bloodstream during dental cleaning and may colonize the heart valves, particularly the mitral and aortic valves, where it is the most common cause of subacute bacterial endocarditis.

Infective endocarditis is often diagnosed clinically with the Duke criteria (www.med-calc.com/endocarditis.html).¹ However, the variability of the clinical presentation and the nonspecific nature of the initial workup often create a diagnostic challenge for the evaluating physician.^1,2

In cases of recurrent persistent fever and a new heart murmur, infective endocarditis must always be considered. Blood cultures should be ordered early and repeatedly. If blood cultures are positive, transesophageal echocardiography should be done without delay if transthoracic echocardiography was unremarkable. Prompt diagnosis and surgical intervention prevent complications.

MITRAL VALVE ANEURYSM IN AORTIC VALVE ENDOCARDITIS

Aortic valve endocarditis often also involves the mitral valve; mitral valve endocarditis is seen in 17% of patients undergoing surgery for aortic valve endocarditis.³ Proposed mechanisms for this association include jet lesions from aortic regurgitation, vegetation prolapse with direct contact between the aortic valve and anterior mitral leaflet (“kissing lesions”), and direct local spread of infection.^4–7

One of every five patients with mitral valve involvement in aortic valve endocarditis has a mitral valve aneurysm.³ This is a serious finding, as it can lead to septic embolization. Also, the weakened lining of the mitral valve aneurysm can rupture, resulting in severe mitral regurgitation, acute pulmonary edema, and precipitous cardiopulmonary decompensation.⁵

Transesophageal echocardiography is more sensitive than transthoracic echocardiography for detecting mitral valve aneurysm.⁸ On two-dimensional echocardiography, the lesion appears as a narrow-necked, saccular echolucency with systolic protrusion into the left atrium. Color Doppler imaging often shows turbulent, high-velocity flow.

Differential diagnosis of mitral valve aneurysm

Differential diagnostic considerations include a valvular blood cyst, a congenital cardiac diverticulum, and mitral valve prolapse.

Valvular blood cysts are extremely rare in adults.⁹ These benign, congenital tumors are most often found on the atrioventricular valves in infants, in whom the reported incidence is between 25% and 100%. In almost all cases, these cysts are believed to regress spontaneously with time.

In almost all reported cases, the cyst involved the valvular apparatus or papillary muscle of the tricuspid, pulmonary, or mitral valve.¹⁰ Cysts consist of a benign diverticulum lined with flattened, cobblestone-shaped endothelium and are filled with blood. They can cause heart murmurs in otherwise asymptomatic patients.

On echocardiography, a blood cyst appears as an oval mass (often at the interatrial septum), often with normal cardiac function. In the rare case in which a blood cyst is found incidentally during echocardiography, the hemodynamic impact, if any, should be determined by Doppler techniques.

When benign, a valvular blood cyst can be safely monitored with echocardiographic follow-up.¹¹ Treatment involves surgical resection of the mass in symptomatic patients in whom cardiac function is impaired by the presence of the cyst.

Congenital cardiac diverticuli are extremely rare, most often seen in children, and associated with a midline thoracoabdominal defect. Echocardiography can differentiate a ventricular diverticulum from an aneurysm or a pseudoaneurysm.

A ventricular diverticulum has a fibrous, narrow neck connecting with the ventricle, and a small circular echo-free space that communicates with the ventricle via this narrow neck.² Doppler imaging shows systolic flow from the diverticulum to the ventricle, and systolic contractility may also be seen during cardiac catheterization. Congenital diverticulum is typically confused with ventricular aneurysm and, to a lesser degree, with mitral valve aneurysm.

Mitral valve prolapse is characterized by interchordal ballooning or hooding of the mitral valve leaflets that occurs when one or both floppy, enlarged leaflets prolapse into the left atrium during systole.

BACK TO OUR PATIENT

The patient underwent open heart surgery, with successful repair of the aortic root, replacement of the aortic valve, and repair of the mitral valve. An abscess was found within the aneurysmal cavity.

A 47-year-old man had had a chronic itch on his back for 2 years. He had no history of trauma to the site, nor did he recall applying topical products to that area.

He was otherwise healthy. He worked as an electrician and said he occasionally experienced cervical and back pain while working.

An examination revealed two grayish-brown ovoid patches on the upper back, each 5 cm to 7 cm in diameter (Figure 1).

DIAGNOSIS: NOTALGIA PARESTHETICA

Chronic, brown-gray, itching patches on the back in an adult patient are characteristic of notalgia paresthetica.

Conditions that may be included in the differential diagnosis but that do not match the presentation in this patient include the following:

• Cutaneous sarcoidosis, which may exhibit several morphologies, but itching would be unusual
• Chronic discoid lupus erythematosus, characterized by scarring and atrophic plaques, but mainly on the face and scalp
• Contact dermatitis, an itchy eczematous condition, characterized by scaly erythematous plaques
• Lichen amyloidosis, a variant of cutaneous amyloidosis characterized by the deposition of amyloid or amyloid-like proteins in the dermis, resulting in red-brown hyperkeratotic lichenoid papules, usually on the pretibial surfaces.

CAUSES AND MANAGEMENT

Notalgia paresthetica is a neuropathic syndrome of the skin of the middle of the back characterized by localized pruritus.^1–3 Although common, it often goes undiagnosed.^1,3,4 It tends to be chronic, with periodic remissions and exacerbations.

Notalgia paresthetica is thought to be a sensory neuropathy and may result from compression of the posterior rami of spinal nerve segments T2 to T6. Slight degenerative changes are often but not always observed, and their clinical significance is uncertain.^1,2,4 The condition affects people of all races and both sexes, usually adults ages 40 to 80.

Clinically, it presents as localized pruritus on the back, usually within the dermatomes T2 to T6.⁵ Examination reveals a hyperpigmented patch, sometimes with excoriations.⁵

Diagnosis is based on clinical findings. Laboratory tests are not useful. Imaging is not needed, but magnetic resonance imaging and evaluation by an orthopedic surgeon are appropriate when there is chronic focal pain. Skin biopsy is usually not necessary, although it may be useful in some patients to exclude other conditions. When biopsy is done, macular amyloidosis or postinflammatory hyperpigmentation is seen.

Treatment is difficult. Topical steroids and oral antihistamines are usually ineffective,⁵ but topical capsaicin may provide temporary relief.³ The most recommended treatment in patients with notalgia paresthetica and underlying spinal disease is evaluation and conservative management of the spinal disease, including progressive exercise and rehabilitation.² Other therapies include oxcarbazepine, gabapentin, transcutaneous electrical nerve stimulation, phototherapy,⁶ and botulinum toxin injection.

TREATMENT OF OUR PATIENT

In our patient, an orthopedic evaluation revealed cervicothoracic scoliosis. He underwent 6 months of conservative treatment under the care of his family physician and a dermatologist. Treatment consisted of exercise and rehabilitation for his scoliosis, and daily application of topical mometasone. The pain and itch gradual improved.

A 47-year-old man had had a chronic itch on his back for 2 years. He had no history of trauma to the site, nor did he recall applying topical products to that area.

He was otherwise healthy. He worked as an electrician and said he occasionally experienced cervical and back pain while working.

An examination revealed two grayish-brown ovoid patches on the upper back, each 5 cm to 7 cm in diameter (Figure 1).

DIAGNOSIS: NOTALGIA PARESTHETICA

Chronic, brown-gray, itching patches on the back in an adult patient are characteristic of notalgia paresthetica.

Conditions that may be included in the differential diagnosis but that do not match the presentation in this patient include the following:

• Cutaneous sarcoidosis, which may exhibit several morphologies, but itching would be unusual
• Chronic discoid lupus erythematosus, characterized by scarring and atrophic plaques, but mainly on the face and scalp
• Contact dermatitis, an itchy eczematous condition, characterized by scaly erythematous plaques
• Lichen amyloidosis, a variant of cutaneous amyloidosis characterized by the deposition of amyloid or amyloid-like proteins in the dermis, resulting in red-brown hyperkeratotic lichenoid papules, usually on the pretibial surfaces.

CAUSES AND MANAGEMENT

Notalgia paresthetica is a neuropathic syndrome of the skin of the middle of the back characterized by localized pruritus.^1–3 Although common, it often goes undiagnosed.^1,3,4 It tends to be chronic, with periodic remissions and exacerbations.

Notalgia paresthetica is thought to be a sensory neuropathy and may result from compression of the posterior rami of spinal nerve segments T2 to T6. Slight degenerative changes are often but not always observed, and their clinical significance is uncertain.^1,2,4 The condition affects people of all races and both sexes, usually adults ages 40 to 80.

Clinically, it presents as localized pruritus on the back, usually within the dermatomes T2 to T6.⁵ Examination reveals a hyperpigmented patch, sometimes with excoriations.⁵

Diagnosis is based on clinical findings. Laboratory tests are not useful. Imaging is not needed, but magnetic resonance imaging and evaluation by an orthopedic surgeon are appropriate when there is chronic focal pain. Skin biopsy is usually not necessary, although it may be useful in some patients to exclude other conditions. When biopsy is done, macular amyloidosis or postinflammatory hyperpigmentation is seen.

Treatment is difficult. Topical steroids and oral antihistamines are usually ineffective,⁵ but topical capsaicin may provide temporary relief.³ The most recommended treatment in patients with notalgia paresthetica and underlying spinal disease is evaluation and conservative management of the spinal disease, including progressive exercise and rehabilitation.² Other therapies include oxcarbazepine, gabapentin, transcutaneous electrical nerve stimulation, phototherapy,⁶ and botulinum toxin injection.

TREATMENT OF OUR PATIENT

In our patient, an orthopedic evaluation revealed cervicothoracic scoliosis. He underwent 6 months of conservative treatment under the care of his family physician and a dermatologist. Treatment consisted of exercise and rehabilitation for his scoliosis, and daily application of topical mometasone. The pain and itch gradual improved.

A 47-year-old man had had a chronic itch on his back for 2 years. He had no history of trauma to the site, nor did he recall applying topical products to that area.

He was otherwise healthy. He worked as an electrician and said he occasionally experienced cervical and back pain while working.

An examination revealed two grayish-brown ovoid patches on the upper back, each 5 cm to 7 cm in diameter (Figure 1).

DIAGNOSIS: NOTALGIA PARESTHETICA

Chronic, brown-gray, itching patches on the back in an adult patient are characteristic of notalgia paresthetica.

Conditions that may be included in the differential diagnosis but that do not match the presentation in this patient include the following:

• Cutaneous sarcoidosis, which may exhibit several morphologies, but itching would be unusual
• Chronic discoid lupus erythematosus, characterized by scarring and atrophic plaques, but mainly on the face and scalp
• Contact dermatitis, an itchy eczematous condition, characterized by scaly erythematous plaques
• Lichen amyloidosis, a variant of cutaneous amyloidosis characterized by the deposition of amyloid or amyloid-like proteins in the dermis, resulting in red-brown hyperkeratotic lichenoid papules, usually on the pretibial surfaces.

CAUSES AND MANAGEMENT

Notalgia paresthetica is a neuropathic syndrome of the skin of the middle of the back characterized by localized pruritus.^1–3 Although common, it often goes undiagnosed.^1,3,4 It tends to be chronic, with periodic remissions and exacerbations.

Notalgia paresthetica is thought to be a sensory neuropathy and may result from compression of the posterior rami of spinal nerve segments T2 to T6. Slight degenerative changes are often but not always observed, and their clinical significance is uncertain.^1,2,4 The condition affects people of all races and both sexes, usually adults ages 40 to 80.

Clinically, it presents as localized pruritus on the back, usually within the dermatomes T2 to T6.⁵ Examination reveals a hyperpigmented patch, sometimes with excoriations.⁵

Diagnosis is based on clinical findings. Laboratory tests are not useful. Imaging is not needed, but magnetic resonance imaging and evaluation by an orthopedic surgeon are appropriate when there is chronic focal pain. Skin biopsy is usually not necessary, although it may be useful in some patients to exclude other conditions. When biopsy is done, macular amyloidosis or postinflammatory hyperpigmentation is seen.

Treatment is difficult. Topical steroids and oral antihistamines are usually ineffective,⁵ but topical capsaicin may provide temporary relief.³ The most recommended treatment in patients with notalgia paresthetica and underlying spinal disease is evaluation and conservative management of the spinal disease, including progressive exercise and rehabilitation.² Other therapies include oxcarbazepine, gabapentin, transcutaneous electrical nerve stimulation, phototherapy,⁶ and botulinum toxin injection.

TREATMENT OF OUR PATIENT

In our patient, an orthopedic evaluation revealed cervicothoracic scoliosis. He underwent 6 months of conservative treatment under the care of his family physician and a dermatologist. Treatment consisted of exercise and rehabilitation for his scoliosis, and daily application of topical mometasone. The pain and itch gradual improved.

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.