Yee Lam, MD, PhD

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; Anne_Mounsey@med.unc.edu

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; Anne_Mounsey@med.unc.edu

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; Anne_Mounsey@med.unc.edu

A 28-year-old woman presents to your office for a routine health maintenance exam. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, clinicians often have tried-and-true favorites. However, some of them may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a two- to four-fold increase in risk for venous thromboembolism (VTE) and an increased risk for myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk for VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk for VTE than other preparations, despite similar estrogen content.⁷ The FDA produced a similar statement that same year, recommending that providers carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks for ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One COC comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks for pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included nearly 5 million women ages 15 to 49, living in France, who had at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks for first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 µg) or high-dose estrogen (30-40 µg) combined with one of five progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI, with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 for PE, 0.82 for ischemic stroke, and 0.56 for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7,143.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs for PE but not arterial events (2.16 for desogestrel and 1.63 for gestodene). For PE, the ARR with levonorgestrel compared to desogestrel and gestodene, respectively, was 19/100,000 and 12/100,000 person-years of use (NNH, 5,263 and 8,333, respectively). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk for PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks for PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen + levonorgestrel confer lowest risk

Prior studies have shown that COCs increase the risk for PE and may also increase the risks for ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk for VTE.^11,12 This study shows that 20 µg of estrogen combined with levonorgestrel is associated with the lowest risks for PE, MI, and ischemic stroke.

CAVEATS

Cohort study, no start date, incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk for VTE is highest in the first three months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not venous thromboembolism, was incomplete; however, in other studies, it has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 µg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[7]:454-456).

A 28-year-old woman presents to your office for a routine health maintenance exam. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, clinicians often have tried-and-true favorites. However, some of them may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a two- to four-fold increase in risk for venous thromboembolism (VTE) and an increased risk for myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk for VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk for VTE than other preparations, despite similar estrogen content.⁷ The FDA produced a similar statement that same year, recommending that providers carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks for ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One COC comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks for pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included nearly 5 million women ages 15 to 49, living in France, who had at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks for first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 µg) or high-dose estrogen (30-40 µg) combined with one of five progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI, with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 for PE, 0.82 for ischemic stroke, and 0.56 for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7,143.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs for PE but not arterial events (2.16 for desogestrel and 1.63 for gestodene). For PE, the ARR with levonorgestrel compared to desogestrel and gestodene, respectively, was 19/100,000 and 12/100,000 person-years of use (NNH, 5,263 and 8,333, respectively). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk for PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks for PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen + levonorgestrel confer lowest risk

Prior studies have shown that COCs increase the risk for PE and may also increase the risks for ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk for VTE.^11,12 This study shows that 20 µg of estrogen combined with levonorgestrel is associated with the lowest risks for PE, MI, and ischemic stroke.

CAVEATS

Cohort study, no start date, incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk for VTE is highest in the first three months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not venous thromboembolism, was incomplete; however, in other studies, it has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 µg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[7]:454-456).

A 28-year-old woman presents to your office for a routine health maintenance exam. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, clinicians often have tried-and-true favorites. However, some of them may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a two- to four-fold increase in risk for venous thromboembolism (VTE) and an increased risk for myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk for VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk for VTE than other preparations, despite similar estrogen content.⁷ The FDA produced a similar statement that same year, recommending that providers carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks for ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One COC comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks for pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included nearly 5 million women ages 15 to 49, living in France, who had at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks for first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 µg) or high-dose estrogen (30-40 µg) combined with one of five progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI, with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 for PE, 0.82 for ischemic stroke, and 0.56 for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7,143.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs for PE but not arterial events (2.16 for desogestrel and 1.63 for gestodene). For PE, the ARR with levonorgestrel compared to desogestrel and gestodene, respectively, was 19/100,000 and 12/100,000 person-years of use (NNH, 5,263 and 8,333, respectively). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk for PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks for PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen + levonorgestrel confer lowest risk

Prior studies have shown that COCs increase the risk for PE and may also increase the risks for ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk for VTE.^11,12 This study shows that 20 µg of estrogen combined with levonorgestrel is associated with the lowest risks for PE, MI, and ischemic stroke.

CAVEATS

Cohort study, no start date, incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk for VTE is highest in the first three months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not venous thromboembolism, was incomplete; however, in other studies, it has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 µg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[7]:454-456).

ILLUSTRATIVE CASE

A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” favorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.⁷ The US Food and Drug Administration (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One combined oral contraceptive comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included just under 5 million women 15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143.

Oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditions

Prior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.^11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is associated with the lowest risks of PE, MI, and ischemic stroke.

CAVEATS

A cohort study, no contraceptive start date, and incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is highest in the first 3 months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Low-dose estrogen is associated with increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” favorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.⁷ The US Food and Drug Administration (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One combined oral contraceptive comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included just under 5 million women 15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143.

Oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditions

Prior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.^11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is associated with the lowest risks of PE, MI, and ischemic stroke.

CAVEATS

A cohort study, no contraceptive start date, and incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is highest in the first 3 months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Low-dose estrogen is associated with increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” favorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.⁷ The US Food and Drug Administration (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One combined oral contraceptive comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included just under 5 million women 15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143.

Oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditions

Prior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.^11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is associated with the lowest risks of PE, MI, and ischemic stroke.

CAVEATS

A cohort study, no contraceptive start date, and incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is highest in the first 3 months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Low-dose estrogen is associated with increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.