Emergency Medicine

Study Overview

Objective. To compare rates of asthma action plan use in limited English proficiency (LEP) caregivers compared with English proficient (EP) caregivers.

Design. Cross-sectional survey.

Participants and setting. A convenience sample of 107 Latino caregivers of children with asthma at an urban academic emergency department (ED). Surveys in the preferred language of the patient (English or Spanish, with the translated version previously validated) were distributed at the time of the ED visit. Interpreters were utilized when requested.

Main outcome measure. Caregiver use of an asthma action plan.

Main results. 51 LEP caregivers and 56 EP caregivers completed the survey. Mothers completed the surveys 87% of the time and the average age of patients was 4 years.  Among the EP caregivers, 64% reported using an asthma action plan, while only 39% of the LEP caregivers reported using one. The difference was statistally significant (P = 0.01). Through both correlations and regressions, English proficiency was the only variable (others included health insurance status and level of caregiver education) that showed a significant effect on asthma action plan use.

Conclusions. Children whose caregiver had LEP were significantly less likely to have and use an asthma action plan. Asthma education in the language of choice of the patient may help improve asthma care.

Commentary

With 20% of US households now speaking a language other than English at home [1], language barriers between providers and patients present multiple challenges to health services delivery and can significantly contribute to immigrant health disparities. Despite US laws and multiple federal agency policies requiring the use of interpreters during health care encounters, organizations continue to fall short of providing interpreter services and often lack adequate or equivalent materials for patient education. Too often, providers overestimate their language skills [2,3], use colleagues as ad hoc interpreters out of convenience [4], or rely on family members for interpretation [4]—a practice that is universally discouraged.

Recent research does suggest that the timing of interpreter use is critical. In planned encounters such as primary care visits, interpreters can and should be scheduled for visits when a language-concordant provider is not available. During hospitalizations, including ED visits, interpreters are most effective when used on admission, during patient teaching, and upon discharge, and the timing of these visits has been shown to affect length of stay and readmission rates [5,6].

This study magnifies the consequences of failing to provide language-concordant services to patients and their caregivers. It also helps to identify one of the sources of pediatric asthma health disparities in Latino populations. The emphasis on the role of the caregiver in action plan utilization is a unique aspect of this study and it is one of the first to examine the issue in this way. It highlights the importance of caregivers in health system transitions and illustrates how a language barrier can potentially impact transitions.

The authors’ explicit use of a power analysis to calculate their sample size is a strength of the study. Furthermore, the authors differentiated their respondents by country of origin, something that rarely occurs in studies of Latinos [7], and allows the reader to differentiate the impact of the intervention at a micro level within this population. The presentation of Spanish language quotes with their translations within the manuscript provides transparency for bilingual readers to verify the accuracy of the authors’ translation.

There are, however, a number of methodological issues that should be noted. The authors acknowledge that they did not account for asthma severity in the survey nor control for it in the analysis, did not assess health literacy, and did not differentiate their results based on country of origin. The latter point is important because the immigration experience and demographic profiles of Latinos differs significantly by country of origin and could factor in to action plan use. The translation process used for survey instrument translation also did not illustrate how it accounted for the well-established linguistic variation that occurs in the Spanish language. Additionally, US census data shows that the main countries of origin of Latinos in the service area of the study are Puerto Rico, Ecuador, and Mexico [1]. The survey itself had Ecuador as a write in and Dominican as a response option. The combination presented in the survey reflects the Latino demographic composition in the nearest large urban area. Thus, when collecting country of origin data on immigrant patients, country choices should reflect local demographics and not national trends for maximum precision.

Another concern is that Spanish language literacy was not assessed. Many Latino immigrants may have limited reading ability in Spanish. For Mexican immigrants in particular, Spanish may be a second language after their indigenous language. This is also true for some South American Latino immigrants from the Andean region. Many Latino immigrants come to the United States with less than an 8th grade education and likely come from educational systems of poor quality, which subsequently affects their Spanish language reading and writing skills [8]. Assessing education level based on US equivalents is not an accurate way to gauge literacy. Thus, assessing reading literacy in Spanish before surveying patients would have been a useful step that could have further refined the results. These factors will have implications for action plan utilization and implementation for any chronic disease.

Providers often think that language barriers are an obvious factor in health disparities and service delivery, but few studies have actually captured or quantified the effects of language barriers on health outcomes. Most studies only identify language barriers as an access issue. This study provides a good illustration of the impact of a language barrier on a known and effective intervention for pediatric asthma management. Practitioners can take the consequences illustrated in this study and easily extrapolate the contribution to health disparities on a broader scale.

Applications for Clinical Practice

Practitioners caring for patients in EDs where the patient or caregiver has a language barrier should make every effort to use appropriate interpreter services when patient teaching occurs. Assessing not only for health literacy but reading ability in the LEP patient or caregiver is also important, since it will affect dyad’s ability to implement self-care measures recommended in patient teaching sessions or action plan implementation. Asking the patient what their country of origin is, regardless of their legal status, will help practitioners refine patient teaching and the language they (and the interpreter when appropriate) use to illustrate what needs to be done to manage their condition.

—Allison Squires, PhD, RN

Study Overview

Objective. To compare rates of asthma action plan use in limited English proficiency (LEP) caregivers compared with English proficient (EP) caregivers.

Design. Cross-sectional survey.

Participants and setting. A convenience sample of 107 Latino caregivers of children with asthma at an urban academic emergency department (ED). Surveys in the preferred language of the patient (English or Spanish, with the translated version previously validated) were distributed at the time of the ED visit. Interpreters were utilized when requested.

Main outcome measure. Caregiver use of an asthma action plan.

Main results. 51 LEP caregivers and 56 EP caregivers completed the survey. Mothers completed the surveys 87% of the time and the average age of patients was 4 years.  Among the EP caregivers, 64% reported using an asthma action plan, while only 39% of the LEP caregivers reported using one. The difference was statistally significant (P = 0.01). Through both correlations and regressions, English proficiency was the only variable (others included health insurance status and level of caregiver education) that showed a significant effect on asthma action plan use.

Conclusions. Children whose caregiver had LEP were significantly less likely to have and use an asthma action plan. Asthma education in the language of choice of the patient may help improve asthma care.

Commentary

With 20% of US households now speaking a language other than English at home [1], language barriers between providers and patients present multiple challenges to health services delivery and can significantly contribute to immigrant health disparities. Despite US laws and multiple federal agency policies requiring the use of interpreters during health care encounters, organizations continue to fall short of providing interpreter services and often lack adequate or equivalent materials for patient education. Too often, providers overestimate their language skills [2,3], use colleagues as ad hoc interpreters out of convenience [4], or rely on family members for interpretation [4]—a practice that is universally discouraged.

Recent research does suggest that the timing of interpreter use is critical. In planned encounters such as primary care visits, interpreters can and should be scheduled for visits when a language-concordant provider is not available. During hospitalizations, including ED visits, interpreters are most effective when used on admission, during patient teaching, and upon discharge, and the timing of these visits has been shown to affect length of stay and readmission rates [5,6].

This study magnifies the consequences of failing to provide language-concordant services to patients and their caregivers. It also helps to identify one of the sources of pediatric asthma health disparities in Latino populations. The emphasis on the role of the caregiver in action plan utilization is a unique aspect of this study and it is one of the first to examine the issue in this way. It highlights the importance of caregivers in health system transitions and illustrates how a language barrier can potentially impact transitions.

The authors’ explicit use of a power analysis to calculate their sample size is a strength of the study. Furthermore, the authors differentiated their respondents by country of origin, something that rarely occurs in studies of Latinos [7], and allows the reader to differentiate the impact of the intervention at a micro level within this population. The presentation of Spanish language quotes with their translations within the manuscript provides transparency for bilingual readers to verify the accuracy of the authors’ translation.

There are, however, a number of methodological issues that should be noted. The authors acknowledge that they did not account for asthma severity in the survey nor control for it in the analysis, did not assess health literacy, and did not differentiate their results based on country of origin. The latter point is important because the immigration experience and demographic profiles of Latinos differs significantly by country of origin and could factor in to action plan use. The translation process used for survey instrument translation also did not illustrate how it accounted for the well-established linguistic variation that occurs in the Spanish language. Additionally, US census data shows that the main countries of origin of Latinos in the service area of the study are Puerto Rico, Ecuador, and Mexico [1]. The survey itself had Ecuador as a write in and Dominican as a response option. The combination presented in the survey reflects the Latino demographic composition in the nearest large urban area. Thus, when collecting country of origin data on immigrant patients, country choices should reflect local demographics and not national trends for maximum precision.

Another concern is that Spanish language literacy was not assessed. Many Latino immigrants may have limited reading ability in Spanish. For Mexican immigrants in particular, Spanish may be a second language after their indigenous language. This is also true for some South American Latino immigrants from the Andean region. Many Latino immigrants come to the United States with less than an 8th grade education and likely come from educational systems of poor quality, which subsequently affects their Spanish language reading and writing skills [8]. Assessing education level based on US equivalents is not an accurate way to gauge literacy. Thus, assessing reading literacy in Spanish before surveying patients would have been a useful step that could have further refined the results. These factors will have implications for action plan utilization and implementation for any chronic disease.

Providers often think that language barriers are an obvious factor in health disparities and service delivery, but few studies have actually captured or quantified the effects of language barriers on health outcomes. Most studies only identify language barriers as an access issue. This study provides a good illustration of the impact of a language barrier on a known and effective intervention for pediatric asthma management. Practitioners can take the consequences illustrated in this study and easily extrapolate the contribution to health disparities on a broader scale.

Applications for Clinical Practice

Practitioners caring for patients in EDs where the patient or caregiver has a language barrier should make every effort to use appropriate interpreter services when patient teaching occurs. Assessing not only for health literacy but reading ability in the LEP patient or caregiver is also important, since it will affect dyad’s ability to implement self-care measures recommended in patient teaching sessions or action plan implementation. Asking the patient what their country of origin is, regardless of their legal status, will help practitioners refine patient teaching and the language they (and the interpreter when appropriate) use to illustrate what needs to be done to manage their condition.

—Allison Squires, PhD, RN

Study Overview

Objective. To compare rates of asthma action plan use in limited English proficiency (LEP) caregivers compared with English proficient (EP) caregivers.

Design. Cross-sectional survey.

Participants and setting. A convenience sample of 107 Latino caregivers of children with asthma at an urban academic emergency department (ED). Surveys in the preferred language of the patient (English or Spanish, with the translated version previously validated) were distributed at the time of the ED visit. Interpreters were utilized when requested.

Main outcome measure. Caregiver use of an asthma action plan.

Main results. 51 LEP caregivers and 56 EP caregivers completed the survey. Mothers completed the surveys 87% of the time and the average age of patients was 4 years.  Among the EP caregivers, 64% reported using an asthma action plan, while only 39% of the LEP caregivers reported using one. The difference was statistally significant (P = 0.01). Through both correlations and regressions, English proficiency was the only variable (others included health insurance status and level of caregiver education) that showed a significant effect on asthma action plan use.

Conclusions. Children whose caregiver had LEP were significantly less likely to have and use an asthma action plan. Asthma education in the language of choice of the patient may help improve asthma care.

Commentary

With 20% of US households now speaking a language other than English at home [1], language barriers between providers and patients present multiple challenges to health services delivery and can significantly contribute to immigrant health disparities. Despite US laws and multiple federal agency policies requiring the use of interpreters during health care encounters, organizations continue to fall short of providing interpreter services and often lack adequate or equivalent materials for patient education. Too often, providers overestimate their language skills [2,3], use colleagues as ad hoc interpreters out of convenience [4], or rely on family members for interpretation [4]—a practice that is universally discouraged.

Recent research does suggest that the timing of interpreter use is critical. In planned encounters such as primary care visits, interpreters can and should be scheduled for visits when a language-concordant provider is not available. During hospitalizations, including ED visits, interpreters are most effective when used on admission, during patient teaching, and upon discharge, and the timing of these visits has been shown to affect length of stay and readmission rates [5,6].

This study magnifies the consequences of failing to provide language-concordant services to patients and their caregivers. It also helps to identify one of the sources of pediatric asthma health disparities in Latino populations. The emphasis on the role of the caregiver in action plan utilization is a unique aspect of this study and it is one of the first to examine the issue in this way. It highlights the importance of caregivers in health system transitions and illustrates how a language barrier can potentially impact transitions.

The authors’ explicit use of a power analysis to calculate their sample size is a strength of the study. Furthermore, the authors differentiated their respondents by country of origin, something that rarely occurs in studies of Latinos [7], and allows the reader to differentiate the impact of the intervention at a micro level within this population. The presentation of Spanish language quotes with their translations within the manuscript provides transparency for bilingual readers to verify the accuracy of the authors’ translation.

There are, however, a number of methodological issues that should be noted. The authors acknowledge that they did not account for asthma severity in the survey nor control for it in the analysis, did not assess health literacy, and did not differentiate their results based on country of origin. The latter point is important because the immigration experience and demographic profiles of Latinos differs significantly by country of origin and could factor in to action plan use. The translation process used for survey instrument translation also did not illustrate how it accounted for the well-established linguistic variation that occurs in the Spanish language. Additionally, US census data shows that the main countries of origin of Latinos in the service area of the study are Puerto Rico, Ecuador, and Mexico [1]. The survey itself had Ecuador as a write in and Dominican as a response option. The combination presented in the survey reflects the Latino demographic composition in the nearest large urban area. Thus, when collecting country of origin data on immigrant patients, country choices should reflect local demographics and not national trends for maximum precision.

Another concern is that Spanish language literacy was not assessed. Many Latino immigrants may have limited reading ability in Spanish. For Mexican immigrants in particular, Spanish may be a second language after their indigenous language. This is also true for some South American Latino immigrants from the Andean region. Many Latino immigrants come to the United States with less than an 8th grade education and likely come from educational systems of poor quality, which subsequently affects their Spanish language reading and writing skills [8]. Assessing education level based on US equivalents is not an accurate way to gauge literacy. Thus, assessing reading literacy in Spanish before surveying patients would have been a useful step that could have further refined the results. These factors will have implications for action plan utilization and implementation for any chronic disease.

Providers often think that language barriers are an obvious factor in health disparities and service delivery, but few studies have actually captured or quantified the effects of language barriers on health outcomes. Most studies only identify language barriers as an access issue. This study provides a good illustration of the impact of a language barrier on a known and effective intervention for pediatric asthma management. Practitioners can take the consequences illustrated in this study and easily extrapolate the contribution to health disparities on a broader scale.

Applications for Clinical Practice

Practitioners caring for patients in EDs where the patient or caregiver has a language barrier should make every effort to use appropriate interpreter services when patient teaching occurs. Assessing not only for health literacy but reading ability in the LEP patient or caregiver is also important, since it will affect dyad’s ability to implement self-care measures recommended in patient teaching sessions or action plan implementation. Asking the patient what their country of origin is, regardless of their legal status, will help practitioners refine patient teaching and the language they (and the interpreter when appropriate) use to illustrate what needs to be done to manage their condition.

—Allison Squires, PhD, RN

ANSWER

The image shows a comminuted and depressed fracture of the lateral tibial plateau. It is depressed approximately 6 to 7 mm. The patient was admitted, and orthopedic consultation was obtained. The patient subsequently underwent an open reduction and internal fixation of the fracture.

ANSWER

The image shows a comminuted and depressed fracture of the lateral tibial plateau. It is depressed approximately 6 to 7 mm. The patient was admitted, and orthopedic consultation was obtained. The patient subsequently underwent an open reduction and internal fixation of the fracture.

ANSWER

The image shows a comminuted and depressed fracture of the lateral tibial plateau. It is depressed approximately 6 to 7 mm. The patient was admitted, and orthopedic consultation was obtained. The patient subsequently underwent an open reduction and internal fixation of the fracture.

A 26-year-old man presented to the emergency department (ED) with a chief complaint of abdominal pain. After triage was complete, he was transported to an examination room, where the clinician obtained the history of presenting illness. The onset of pain was approximately 90 minutes prior to arrival at the ED and woke the patient from a “sound sleep.”  He stated that the pain initially started as a “3 out of 10” but had progressed to a “12 out of 10,” and he described it as being in the right lower quadrant of his abdomen, with radiation to his right testicle. However, he was unsure where the pain started or if it was worse in either location. Nausea was the primary associated symptom, but he denied vomiting, diarrhea, fever, dysuria, or hematuria. Last, the patient denied history of trauma.   

Medical history was noncontributory: He denied previous gastrointestinal diseases, and there was no history of renal stones, urinary tract infection, or any other genitourinary disease. He had no surgical history. The patient smoked less than a pack of cigarettes per day but denied alcohol or drug use.

Physical examination revealed a young man in moderate discomfort. Despite describing his pain as a “12 out of 10,” he had a blood pressure of 121/72 mm Hg; pulse, 59 beats/min; respiratory rate, 20 breaths/min; and temperature, 96.8°F. HEENT and cardiovascular, respiratory, musculoskeletal, and neurologic exam results were all within normal limits. Abdominal examination revealed a mildly tender right lower quadrant with deep palpation, but no rebound or guarding. Murphy sign was negative.

Because of the complaint of pain radiating to the testicles, a genitourinary examination was performed. The penis appeared unremarkable, with no lesions or discharge. There was no inguinal lymphadenopathy. The scrotum appeared appropriate in size and was also grossly unremarkable. The left testicle was nontender. However, palpation of the right testicle elicited moderate to severe pain. There was no visible swelling, and there were no palpable hernias or other masses. Cremasteric reflex was assessed bilaterally and deemed to be absent on the right side.

A workup was initiated that included a complete blood count, comprehensive metabolic panel, and urinalysis; the results of these tests were unremarkable. A differential diagnosis was formed, with emphasis on appendicitis and testicular torsion. Because of the specific nature and location of the pain, both ultrasound and CT of the abdomen/pelvis were considered. It was decided to order the ultrasound, with a plan to perform CT only if ultrasound was unremarkable. The patient was medicated for his pain and the ultrasound commenced. Halfway through the imaging, the clinician and attending physician were summoned to the examination room to review the image seen in Figure 1.

On the next page: Discussion and diagnosis >>

DISCUSSION

Testicular torsion may occur if the testicle twists or rotates on the spermatic cord. The twisting causes arterial ischemia and venous outflow obstruction, cutting off the testicle’s blood supply.^1,2 Torsion may be extravaginal or intravaginal, depending on the extent of involvement of the surrounding structures.²

Extravaginal torsion is most commonly seen in neonates and occurs because the entire testicle may freely rotate prior to fixation to the scrotal wall via the tunica vaginalis.²Intravaginal torsion is more common in adolescents and often occurs as a result of a condition known as bell clapper deformity. This congenital abnormality enables the testicle to rotate within the tunica vaginalis and rest transversely in the scrotum instead of in a more vertical orientation.^2,3 Torsion occurs if the testicle rotates 90° to 180°, with complete torsion occurring at 360° (torsion may extend to as much as 720°).² Torsion may also occur as a result of trauma.¹

Peak incidence of testicular torsion occurs at ages 13 to 14, but it can occur at any age; torsion affects approximately 1 in 4,000 males younger than 25.^2-5 Ninety-five percent of all torsions are intravaginal.² Torsion is the most common pathology for males who undergo surgical exploration for scrotal pain.³

The main goal in the diagnosis and treatment of torsion is testicular salvage. Torsion is considered a urologic emergency, making early diagnosis and treatment critical to prevent testicular loss. In fact, a review of the relevant literature reveals that the rate of testicular salvage is much higher if the diagnosis is made within 6 to 12 hours.^1,2,5 Potential sequelae from delayed treatment include testicular infarction, loss of testicle, infertility problems, infections, cosmetic deformity, and increased risk for testicular malignancy.²

Because many men hesitate to seek medical attention for symptoms of testicular pain and swelling, the primary care clinician should openly discuss testicular disorders, especially with preadolescent males, during testicular examinations.⁶

Diagnosis

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. The cremasteric reflex should be assessed because it can help differentiate among the causes of testicular pain.⁷ It is performed by gently stroking the upper inner thigh and observing for contraction of the ipsilateral testicle. One study found that, in cases of torsion, the absence of a cremasteric reflex had a sensitivity of 96% and a specificity of 88%.⁷ See the Table for the differential diagnosis for acute testicular pain.

While it is often possible to make the diagnosis of testicular torsion clinically, ultrasound with color Doppler is the diagnostic test of choice in cases for which the cause of acute scrotal pain is unclear.⁸ Ultrasound provides anatomic detail of the scrotum and its contents, and perfusion is assessed by adding the color Doppler images.⁸ It is important to note that, while the absence of blood flow is considered diagnostic for testicular torsion, the presence of flow does not necessarily exclude it.⁴

On the next page: Treatment >>

Treatment

Surgical exploration with intraoperative detorsion and orchiopexy (fixation of the testicle to the scrotal wall) is the mainstay of treatment for testicular torsion.¹ Orchiopexy is often performed bilaterally in order to prevent future torsion of the unaffected testicle. In about 40% of males with the bell clapper deformity, the condition is present on both sides.² Orchiectomy, the complete removal of the testicle, is necessary when the degree of torsion and subsequent ischemia have caused irreversible damage to the testicle.⁶ In one study in which 2,248 cases of torsion were reviewed, approximately 34% of males required orchiectomy.⁶

If surgery may be delayed, the clinician may attempt manual detorsion at the bedside. Despite the “open book” method described in many texts—which instructs the practitioner to rotate the testicle laterally—a review of the literature reveals that torsion takes place medially only 70% of the time.^1,5 The clinician should always consider this when any attempts at manual detorsion are made and correlate his or her technique with physical examination and the patient’s response.⁵

Relief of pain and return of the testicle to its natural longitudinal lie are considered indicators of successful detorsion.¹ Color Doppler ultrasound should be used to confirm the return of circulation. However, in one case review of pediatric patients who underwent surgical exploration after manual detorsion, some degree of residual torsion remained in 32%.⁵ Because of this risk, surgery is still indicated even in cases of successful bedside detorsion.⁵

On the next page: Case continuation >> 

CASE CONTINUATION

The decision to perform bedside ultrasound was made because the diagnosis of testicular torsion is a surgical emergency, and the window of time to prevent complications can be extremely narrow. If the ultrasound had been normal, then a CT scan may have provided additional data on which to base the diagnosis.

The patient was given adequate parenteral pain medication. After color Doppler ultrasound confirmed the torsion, the testicle was laterally rotated approximately 360°. The patient reported alleviation of his symptoms. Color Doppler was again performed to confirm the return of hyperemic blood flow to the affected testicle (Figure 2). The urologist arrived shortly thereafter and the patient was taken to the operating room, where he underwent scrotal exploration and bilateral orchiopexy.

On the next page: Conclusion >>

CONCLUSION

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. Testicular torsion is most commonly seen in infants and adolescents but can occur at any age. The condition is a surgical emergency and the goal is testicular salvage, which is most likely to occur before 12 hours have elapsed since the onset of symptoms. An important component of the physical examination is attempting to elicit the cremasteric reflex, which is likely to be absent in the presence of torsion.

The primary care provider’s goal is to rapidly diagnose testicular torsion, then refer the patient immediately to a urologist or ED. The skilled clinician may attempt manual detorsion, based on his/her expertise and comfort level; however, this procedure should never delay prompt surgical intervention.

REFERENCES

1. Eyre RC. Evaluation of the acute scrotum in adults. www.uptodate.com/contents/evaluation-of-the-acute-scrotum-in-adults. Accessed May 16, 2014.

2. Ogunyemi OI, Weiker M, Abel EJ. Testicular torsion. http://emedicine.medscape.com/article/2036003-overview. Accessed May 16, 2014.

3. Khan F, Muoka O, Watson GM. Bell clapper testis, torsion, and detorsion: a case report. Case Rep Urol. 2011;2011:631970.

4. Molokwu CN, Somani BK, Goodman CM. Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. BJU Int. 2011;107(6):990-993.

5. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003;169(2):663-665.

6. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005;159:1167-1171.

7. Schmitz D, Safranek S. How useful is a physical exam in diagnosing testicular torsion? J Fam Pract. 2009;58(8):433-434.

8. D’Andrea A, Coppolino F, Cesarano E, et al. US in the assessment of acute scrotum. Crit Ultrasound J. 2013;5(suppl 1):S8. www.criticalultrasound journal.com/content/5/S1/S8/. Accessed May 16, 2014.

A 26-year-old man presented to the emergency department (ED) with a chief complaint of abdominal pain. After triage was complete, he was transported to an examination room, where the clinician obtained the history of presenting illness. The onset of pain was approximately 90 minutes prior to arrival at the ED and woke the patient from a “sound sleep.”  He stated that the pain initially started as a “3 out of 10” but had progressed to a “12 out of 10,” and he described it as being in the right lower quadrant of his abdomen, with radiation to his right testicle. However, he was unsure where the pain started or if it was worse in either location. Nausea was the primary associated symptom, but he denied vomiting, diarrhea, fever, dysuria, or hematuria. Last, the patient denied history of trauma.   

Medical history was noncontributory: He denied previous gastrointestinal diseases, and there was no history of renal stones, urinary tract infection, or any other genitourinary disease. He had no surgical history. The patient smoked less than a pack of cigarettes per day but denied alcohol or drug use.

Physical examination revealed a young man in moderate discomfort. Despite describing his pain as a “12 out of 10,” he had a blood pressure of 121/72 mm Hg; pulse, 59 beats/min; respiratory rate, 20 breaths/min; and temperature, 96.8°F. HEENT and cardiovascular, respiratory, musculoskeletal, and neurologic exam results were all within normal limits. Abdominal examination revealed a mildly tender right lower quadrant with deep palpation, but no rebound or guarding. Murphy sign was negative.

Because of the complaint of pain radiating to the testicles, a genitourinary examination was performed. The penis appeared unremarkable, with no lesions or discharge. There was no inguinal lymphadenopathy. The scrotum appeared appropriate in size and was also grossly unremarkable. The left testicle was nontender. However, palpation of the right testicle elicited moderate to severe pain. There was no visible swelling, and there were no palpable hernias or other masses. Cremasteric reflex was assessed bilaterally and deemed to be absent on the right side.

A workup was initiated that included a complete blood count, comprehensive metabolic panel, and urinalysis; the results of these tests were unremarkable. A differential diagnosis was formed, with emphasis on appendicitis and testicular torsion. Because of the specific nature and location of the pain, both ultrasound and CT of the abdomen/pelvis were considered. It was decided to order the ultrasound, with a plan to perform CT only if ultrasound was unremarkable. The patient was medicated for his pain and the ultrasound commenced. Halfway through the imaging, the clinician and attending physician were summoned to the examination room to review the image seen in Figure 1.

On the next page: Discussion and diagnosis >>

DISCUSSION

Testicular torsion may occur if the testicle twists or rotates on the spermatic cord. The twisting causes arterial ischemia and venous outflow obstruction, cutting off the testicle’s blood supply.^1,2 Torsion may be extravaginal or intravaginal, depending on the extent of involvement of the surrounding structures.²

Extravaginal torsion is most commonly seen in neonates and occurs because the entire testicle may freely rotate prior to fixation to the scrotal wall via the tunica vaginalis.²Intravaginal torsion is more common in adolescents and often occurs as a result of a condition known as bell clapper deformity. This congenital abnormality enables the testicle to rotate within the tunica vaginalis and rest transversely in the scrotum instead of in a more vertical orientation.^2,3 Torsion occurs if the testicle rotates 90° to 180°, with complete torsion occurring at 360° (torsion may extend to as much as 720°).² Torsion may also occur as a result of trauma.¹

Peak incidence of testicular torsion occurs at ages 13 to 14, but it can occur at any age; torsion affects approximately 1 in 4,000 males younger than 25.^2-5 Ninety-five percent of all torsions are intravaginal.² Torsion is the most common pathology for males who undergo surgical exploration for scrotal pain.³

The main goal in the diagnosis and treatment of torsion is testicular salvage. Torsion is considered a urologic emergency, making early diagnosis and treatment critical to prevent testicular loss. In fact, a review of the relevant literature reveals that the rate of testicular salvage is much higher if the diagnosis is made within 6 to 12 hours.^1,2,5 Potential sequelae from delayed treatment include testicular infarction, loss of testicle, infertility problems, infections, cosmetic deformity, and increased risk for testicular malignancy.²

Because many men hesitate to seek medical attention for symptoms of testicular pain and swelling, the primary care clinician should openly discuss testicular disorders, especially with preadolescent males, during testicular examinations.⁶

Diagnosis

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. The cremasteric reflex should be assessed because it can help differentiate among the causes of testicular pain.⁷ It is performed by gently stroking the upper inner thigh and observing for contraction of the ipsilateral testicle. One study found that, in cases of torsion, the absence of a cremasteric reflex had a sensitivity of 96% and a specificity of 88%.⁷ See the Table for the differential diagnosis for acute testicular pain.

While it is often possible to make the diagnosis of testicular torsion clinically, ultrasound with color Doppler is the diagnostic test of choice in cases for which the cause of acute scrotal pain is unclear.⁸ Ultrasound provides anatomic detail of the scrotum and its contents, and perfusion is assessed by adding the color Doppler images.⁸ It is important to note that, while the absence of blood flow is considered diagnostic for testicular torsion, the presence of flow does not necessarily exclude it.⁴

On the next page: Treatment >>

Treatment

Surgical exploration with intraoperative detorsion and orchiopexy (fixation of the testicle to the scrotal wall) is the mainstay of treatment for testicular torsion.¹ Orchiopexy is often performed bilaterally in order to prevent future torsion of the unaffected testicle. In about 40% of males with the bell clapper deformity, the condition is present on both sides.² Orchiectomy, the complete removal of the testicle, is necessary when the degree of torsion and subsequent ischemia have caused irreversible damage to the testicle.⁶ In one study in which 2,248 cases of torsion were reviewed, approximately 34% of males required orchiectomy.⁶

If surgery may be delayed, the clinician may attempt manual detorsion at the bedside. Despite the “open book” method described in many texts—which instructs the practitioner to rotate the testicle laterally—a review of the literature reveals that torsion takes place medially only 70% of the time.^1,5 The clinician should always consider this when any attempts at manual detorsion are made and correlate his or her technique with physical examination and the patient’s response.⁵

Relief of pain and return of the testicle to its natural longitudinal lie are considered indicators of successful detorsion.¹ Color Doppler ultrasound should be used to confirm the return of circulation. However, in one case review of pediatric patients who underwent surgical exploration after manual detorsion, some degree of residual torsion remained in 32%.⁵ Because of this risk, surgery is still indicated even in cases of successful bedside detorsion.⁵

On the next page: Case continuation >> 

CASE CONTINUATION

The decision to perform bedside ultrasound was made because the diagnosis of testicular torsion is a surgical emergency, and the window of time to prevent complications can be extremely narrow. If the ultrasound had been normal, then a CT scan may have provided additional data on which to base the diagnosis.

The patient was given adequate parenteral pain medication. After color Doppler ultrasound confirmed the torsion, the testicle was laterally rotated approximately 360°. The patient reported alleviation of his symptoms. Color Doppler was again performed to confirm the return of hyperemic blood flow to the affected testicle (Figure 2). The urologist arrived shortly thereafter and the patient was taken to the operating room, where he underwent scrotal exploration and bilateral orchiopexy.

On the next page: Conclusion >>

CONCLUSION

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. Testicular torsion is most commonly seen in infants and adolescents but can occur at any age. The condition is a surgical emergency and the goal is testicular salvage, which is most likely to occur before 12 hours have elapsed since the onset of symptoms. An important component of the physical examination is attempting to elicit the cremasteric reflex, which is likely to be absent in the presence of torsion.

The primary care provider’s goal is to rapidly diagnose testicular torsion, then refer the patient immediately to a urologist or ED. The skilled clinician may attempt manual detorsion, based on his/her expertise and comfort level; however, this procedure should never delay prompt surgical intervention.

REFERENCES

1. Eyre RC. Evaluation of the acute scrotum in adults. www.uptodate.com/contents/evaluation-of-the-acute-scrotum-in-adults. Accessed May 16, 2014.

2. Ogunyemi OI, Weiker M, Abel EJ. Testicular torsion. http://emedicine.medscape.com/article/2036003-overview. Accessed May 16, 2014.

3. Khan F, Muoka O, Watson GM. Bell clapper testis, torsion, and detorsion: a case report. Case Rep Urol. 2011;2011:631970.

4. Molokwu CN, Somani BK, Goodman CM. Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. BJU Int. 2011;107(6):990-993.

5. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003;169(2):663-665.

6. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005;159:1167-1171.

7. Schmitz D, Safranek S. How useful is a physical exam in diagnosing testicular torsion? J Fam Pract. 2009;58(8):433-434.

8. D’Andrea A, Coppolino F, Cesarano E, et al. US in the assessment of acute scrotum. Crit Ultrasound J. 2013;5(suppl 1):S8. www.criticalultrasound journal.com/content/5/S1/S8/. Accessed May 16, 2014.

A 26-year-old man presented to the emergency department (ED) with a chief complaint of abdominal pain. After triage was complete, he was transported to an examination room, where the clinician obtained the history of presenting illness. The onset of pain was approximately 90 minutes prior to arrival at the ED and woke the patient from a “sound sleep.”  He stated that the pain initially started as a “3 out of 10” but had progressed to a “12 out of 10,” and he described it as being in the right lower quadrant of his abdomen, with radiation to his right testicle. However, he was unsure where the pain started or if it was worse in either location. Nausea was the primary associated symptom, but he denied vomiting, diarrhea, fever, dysuria, or hematuria. Last, the patient denied history of trauma.   

Medical history was noncontributory: He denied previous gastrointestinal diseases, and there was no history of renal stones, urinary tract infection, or any other genitourinary disease. He had no surgical history. The patient smoked less than a pack of cigarettes per day but denied alcohol or drug use.

Physical examination revealed a young man in moderate discomfort. Despite describing his pain as a “12 out of 10,” he had a blood pressure of 121/72 mm Hg; pulse, 59 beats/min; respiratory rate, 20 breaths/min; and temperature, 96.8°F. HEENT and cardiovascular, respiratory, musculoskeletal, and neurologic exam results were all within normal limits. Abdominal examination revealed a mildly tender right lower quadrant with deep palpation, but no rebound or guarding. Murphy sign was negative.

Because of the complaint of pain radiating to the testicles, a genitourinary examination was performed. The penis appeared unremarkable, with no lesions or discharge. There was no inguinal lymphadenopathy. The scrotum appeared appropriate in size and was also grossly unremarkable. The left testicle was nontender. However, palpation of the right testicle elicited moderate to severe pain. There was no visible swelling, and there were no palpable hernias or other masses. Cremasteric reflex was assessed bilaterally and deemed to be absent on the right side.

A workup was initiated that included a complete blood count, comprehensive metabolic panel, and urinalysis; the results of these tests were unremarkable. A differential diagnosis was formed, with emphasis on appendicitis and testicular torsion. Because of the specific nature and location of the pain, both ultrasound and CT of the abdomen/pelvis were considered. It was decided to order the ultrasound, with a plan to perform CT only if ultrasound was unremarkable. The patient was medicated for his pain and the ultrasound commenced. Halfway through the imaging, the clinician and attending physician were summoned to the examination room to review the image seen in Figure 1.

On the next page: Discussion and diagnosis >>

DISCUSSION

Testicular torsion may occur if the testicle twists or rotates on the spermatic cord. The twisting causes arterial ischemia and venous outflow obstruction, cutting off the testicle’s blood supply.^1,2 Torsion may be extravaginal or intravaginal, depending on the extent of involvement of the surrounding structures.²

Extravaginal torsion is most commonly seen in neonates and occurs because the entire testicle may freely rotate prior to fixation to the scrotal wall via the tunica vaginalis.²Intravaginal torsion is more common in adolescents and often occurs as a result of a condition known as bell clapper deformity. This congenital abnormality enables the testicle to rotate within the tunica vaginalis and rest transversely in the scrotum instead of in a more vertical orientation.^2,3 Torsion occurs if the testicle rotates 90° to 180°, with complete torsion occurring at 360° (torsion may extend to as much as 720°).² Torsion may also occur as a result of trauma.¹

Peak incidence of testicular torsion occurs at ages 13 to 14, but it can occur at any age; torsion affects approximately 1 in 4,000 males younger than 25.^2-5 Ninety-five percent of all torsions are intravaginal.² Torsion is the most common pathology for males who undergo surgical exploration for scrotal pain.³

The main goal in the diagnosis and treatment of torsion is testicular salvage. Torsion is considered a urologic emergency, making early diagnosis and treatment critical to prevent testicular loss. In fact, a review of the relevant literature reveals that the rate of testicular salvage is much higher if the diagnosis is made within 6 to 12 hours.^1,2,5 Potential sequelae from delayed treatment include testicular infarction, loss of testicle, infertility problems, infections, cosmetic deformity, and increased risk for testicular malignancy.²

Because many men hesitate to seek medical attention for symptoms of testicular pain and swelling, the primary care clinician should openly discuss testicular disorders, especially with preadolescent males, during testicular examinations.⁶

Diagnosis

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. The cremasteric reflex should be assessed because it can help differentiate among the causes of testicular pain.⁷ It is performed by gently stroking the upper inner thigh and observing for contraction of the ipsilateral testicle. One study found that, in cases of torsion, the absence of a cremasteric reflex had a sensitivity of 96% and a specificity of 88%.⁷ See the Table for the differential diagnosis for acute testicular pain.

While it is often possible to make the diagnosis of testicular torsion clinically, ultrasound with color Doppler is the diagnostic test of choice in cases for which the cause of acute scrotal pain is unclear.⁸ Ultrasound provides anatomic detail of the scrotum and its contents, and perfusion is assessed by adding the color Doppler images.⁸ It is important to note that, while the absence of blood flow is considered diagnostic for testicular torsion, the presence of flow does not necessarily exclude it.⁴

On the next page: Treatment >>

Treatment

Surgical exploration with intraoperative detorsion and orchiopexy (fixation of the testicle to the scrotal wall) is the mainstay of treatment for testicular torsion.¹ Orchiopexy is often performed bilaterally in order to prevent future torsion of the unaffected testicle. In about 40% of males with the bell clapper deformity, the condition is present on both sides.² Orchiectomy, the complete removal of the testicle, is necessary when the degree of torsion and subsequent ischemia have caused irreversible damage to the testicle.⁶ In one study in which 2,248 cases of torsion were reviewed, approximately 34% of males required orchiectomy.⁶

If surgery may be delayed, the clinician may attempt manual detorsion at the bedside. Despite the “open book” method described in many texts—which instructs the practitioner to rotate the testicle laterally—a review of the literature reveals that torsion takes place medially only 70% of the time.^1,5 The clinician should always consider this when any attempts at manual detorsion are made and correlate his or her technique with physical examination and the patient’s response.⁵

Relief of pain and return of the testicle to its natural longitudinal lie are considered indicators of successful detorsion.¹ Color Doppler ultrasound should be used to confirm the return of circulation. However, in one case review of pediatric patients who underwent surgical exploration after manual detorsion, some degree of residual torsion remained in 32%.⁵ Because of this risk, surgery is still indicated even in cases of successful bedside detorsion.⁵

On the next page: Case continuation >> 

CASE CONTINUATION

The decision to perform bedside ultrasound was made because the diagnosis of testicular torsion is a surgical emergency, and the window of time to prevent complications can be extremely narrow. If the ultrasound had been normal, then a CT scan may have provided additional data on which to base the diagnosis.

The patient was given adequate parenteral pain medication. After color Doppler ultrasound confirmed the torsion, the testicle was laterally rotated approximately 360°. The patient reported alleviation of his symptoms. Color Doppler was again performed to confirm the return of hyperemic blood flow to the affected testicle (Figure 2). The urologist arrived shortly thereafter and the patient was taken to the operating room, where he underwent scrotal exploration and bilateral orchiopexy.

On the next page: Conclusion >>

CONCLUSION

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. Testicular torsion is most commonly seen in infants and adolescents but can occur at any age. The condition is a surgical emergency and the goal is testicular salvage, which is most likely to occur before 12 hours have elapsed since the onset of symptoms. An important component of the physical examination is attempting to elicit the cremasteric reflex, which is likely to be absent in the presence of torsion.

The primary care provider’s goal is to rapidly diagnose testicular torsion, then refer the patient immediately to a urologist or ED. The skilled clinician may attempt manual detorsion, based on his/her expertise and comfort level; however, this procedure should never delay prompt surgical intervention.

REFERENCES

1. Eyre RC. Evaluation of the acute scrotum in adults. www.uptodate.com/contents/evaluation-of-the-acute-scrotum-in-adults. Accessed May 16, 2014.

2. Ogunyemi OI, Weiker M, Abel EJ. Testicular torsion. http://emedicine.medscape.com/article/2036003-overview. Accessed May 16, 2014.

3. Khan F, Muoka O, Watson GM. Bell clapper testis, torsion, and detorsion: a case report. Case Rep Urol. 2011;2011:631970.

4. Molokwu CN, Somani BK, Goodman CM. Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. BJU Int. 2011;107(6):990-993.

5. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003;169(2):663-665.

6. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005;159:1167-1171.

7. Schmitz D, Safranek S. How useful is a physical exam in diagnosing testicular torsion? J Fam Pract. 2009;58(8):433-434.

8. D’Andrea A, Coppolino F, Cesarano E, et al. US in the assessment of acute scrotum. Crit Ultrasound J. 2013;5(suppl 1):S8. www.criticalultrasound journal.com/content/5/S1/S8/. Accessed May 16, 2014.

A 20-year-old woman presents to the emergency department with fatigue and the sudden onset of palpitations. She reports no history of significant illness or surgery. She says she is not currently taking prescription or over-the-counter medications. She does not smoke, drink alcohol, or use illicit drugs.

Her weight is 52 kg (115 lb), her height is 170 cm (67 in), and her body mass index (BMI) is 18 kg/m². Vital signs: temperature 35.7°C (96.4°F), blood pressure 92/48 mm Hg, heart rate 73 bpm, respiratory rate 5 breaths per minute, and oxygen saturation 98% on room air.

She appears tired but is alert, conversant, and cooperative. Her skin is normal, and dentition is fair. Her pulse is regular, and respirations are slow. The abdomen is soft, non-tender, and flat. Strength is 4 on a scale of 5 in all extremities. Deep-tendon reflexes are 2+ and symmetric.

Electrocardiography (Figure 1) in the emergency department shows ST-segment depression, a prolonged corrected QT interval of 665 msec, T-wave inversion, PR prolongation, increased P-wave amplitude, and U waves.

1. Which electrolyte abnormality is associated with this electrocardiographic picture?

• Hypercalcemia
• Hyperkalemia
• Hypocalcemia
• Hypokalemia

Hypokalemia is the likely cause of these findings. The finding of U waves is considered significant when they are inverted, merged with the T wave, or have an amplitude greater than the T wave.¹ U waves are best seen in the precordial leads. When severe, hypokalemia can lead to potentially fatal arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, and ventricular fibrillation.²

Hyperkalemia is associated with peaked T waves, a prolonged PR interval, decreased P wave amplitude, and a widened QRS complex.² When acute and severe, hyperkalemia is associated with ventricular arrhythmia.

Hypocalcemia is associated with a prolonged QT interval and ventricular dysrhythmia, but not U waves.²

Hypercalcemia is associated with bradydysrhythmia, as well as with a shortened QT interval.²

LABORATORY TESTING

Laboratory testing shows the following:

• Sodium 126 mmol/L (reference range 135–145)
• Potassium 1.5 mmol/L (3.5–5.1)
• Chloride 58 mmol/L (100–110)
• Bicarbonate 62 mmol/L (20–30)
• Blood urea nitrogen 16 mg/dL (7–18)
• Creatinine 0.8 mg/dL (0.5–1.0)
• Glucose 106 mg/dL (70–110)
• Ionized calcium 4.4 mg/dL (4.5–5.3)
• Magnesium 1.8 mg/dL (1.7–2.3)
• Phosphorus 4.1 mg/dL (2.5–4.5)
• Venous blood gases pH 7.56 (7.35–7.45), Pco₂ 69 mm Hg (35–45).

POTASSIUM HOMEOSTASIS

Ninety-eight percent of potassium is intracellular and only 2% is extracellular.³ The main cellular stores are myocytes and hepatocytes. Patients with decreased muscle mass may be at a higher risk of hypokalemia as a result of decreased skeletal muscle stores.⁴

The acute development of hypokalemia occurs from transcellular shifts. Alkalosis, insulin secretion, and beta-adrenergic stimulation promote the intracellular uptake of potassium. The major hormonal regulator of potassium excretion is aldosterone, which is stimulated by renal hypoperfusion and promotes potassium-ion secretion in the distal convoluted tubule.

Chronic hypokalemia develops in patients with ongoing renal or gastrointestinal potassium loss. If the cause of potassium loss is not elucidated by the history, the physical, and a review of medications, then one of two things is possible: either the patient has renal tubular disease affecting acid-base and potassium regulation, causing excessive mineralocorticoid secretion, which is associated with an abnormal response to aldosterone; or the patient is not being forthcoming in the history.

2. Which is the most likely cause of hypokalemia in this patient?

• Vomiting
• Liddle syndrome
• Bartter syndrome
• Gitelman syndrome
• Diuretic use

Her laboratory tests reveal hypokalemia and hyponatremic-hypochloremic metabolic alkalosis with compensatory respiratory acidosis. In metabolic alkalosis, the expected respiratory compensation is an increase of 0.7 mm Hg in Pco₂ for each 1-mEq/L increase in bicarbonate. Therefore, the expected Pco₂ is 67, close to the patient’s actual value of 69.

Protracted vomiting with loss of gastric acid juices could be a cause of the metabolic disturbances in this young woman, although she did not mention vomiting during the history.

Liddle syndrome, or pseudoaldosteronism, is a rare autosomal dominant disorder characterized by altered renal epithelial sodium channels, excessive sodium retention, and resultant hypertension. Hypokalemia and alkalosis are seen in Liddle syndrome, but the absence of hypertension in our patient makes Liddle syndrome unlikely.

Bartter syndrome is an inherited autosomal recessive disorder of the sodium-potassium-chloride cotransporter in the thick ascending loop of Henle, resulting in impaired reabsorption of chloride and sodium. Bartter syndrome mimics chronic loop-diuretic use and is associated with hypercalciuria. Bartter syndrome is possible in this patient; however, patients with Bartter syndrome are usually diagnosed in infancy or childhood and have evidence of growth impairment.

Gitelman syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride cotransporter. Although Gitelman syndrome is more common than Bartter syndrome and presents at older ages, it is not usually associated with such profound metabolic alkalosis. Gitelman syndrome mimics chronic use of thiazide diuretics and is associated with hypocalciuria.

Diuretic use could also cause the metabolic disturbances described; however, the patient denied taking diuretics.

The most common cause of hypokalemia in clinical practice is diuretic use.⁴ In this young woman with unexplained hypokalemia, the most likely cause is either undisclosed self-induced vomiting or diuretic abuse. The degree of metabolic alkalosis suggests vomiting, since metabolic alkalosis this severe is usually seen only with protracted vomiting. Bartter and Gitelman syndromes are included in the differential diagnosis, but they are much less common than hypokalemia associated with diuretics or self-induced vomiting.⁵

3. Which test could help elucidate the cause of hypokalemia in this patient?

• Ratio of plasma aldosterone to rennin
• Urine chloride
• Ratio of urinary potassium to creatinine
• Urinary anion gap and urinary pH

APPROACH TO HYPOKALEMIA

Determining the cause of hypokalemia starts with a thorough history and physical examination. The history should focus on drugs such as diuretics and laxatives. Women should be asked about their menstrual history since irregular periods may suggest an eating disorder. The physical examination should focus on signs that suggest self-induced vomiting, such as dry skin, dental erosions, enlarged parotid glands, and calluses or scars on the knuckles.

Patients with an unclear cause of hypokalemia after a thorough history and physical examination can be categorized into one of three groups based on blood pressure and acid-base status:

• Hypokalemia, hypertension, metabolic alkalosis
• Hypokalemia, normal blood pressure, metabolic acidosis
• Hypokalemia, normal blood pressure, metabolic alkalosis.

Hypokalemia, hypertension, metabolic alkalosis

The blood pressure provides an important clue in the evaluation of hypokalemia. The combination of hypertension, hypokalemia, and alkalosis should raise concern for hyperaldosteronism or pseudoaldosteronism. Primary hyperaldosteronism from an adrenal adenoma (Conn syndrome) is characterized by a plasma aldosterone-renin ratio of greater than 20.^6,7 In contrast, patients with secondary hyperaldosteronism due to renovascular disease have a plasma aldosterone-renin ratio of less than 10. Patients with pseudoaldosteronism have low aldosterone and renin levels and hypertension. Since our patient has a normal blood pressure, testing the plasma aldosterone and renin levels would not help determine the cause of her hypokalemia.

Hypokalemia, normal blood pressure, metabolic acidosis

Patients with normal blood pressure, hypokalemia, and normal plasma anion gap acidosis either have renal tubular acidosis or have lost potassium because of diarrhea or laxative abuse. In a patient who denies taking laxatives or denies a history of diarrhea, checking the urinary anion gap and urinary pH may help differentiate the cause of acidosis and hypokalemia.

The urinary anion gap, calculated by the equation sodium + potassium − chloride, is an indirect estimate of hydrogen excretion in the form of ammonium ion⁸; the normal value is 0 to 10 mEq/L. A negative value represents increased hydrogen excretion in response to systemic acidosis from gastrointestinal or renal loss of bicarbonate (proximal renal tubular acidosis). A urinary pH greater than 5.5 in the setting of systemic acidosis suggests impaired ability of the kidneys to acidify urine and raises the possibility of renal tubular acidosis.

This patient has metabolic alkalosis, so calculation of the urinary anion gap would not be helpful.

Hypokalemia, normal blood pressure, metabolic alkalosis

Patients such as ours, with normal blood pressure, hypokalemia, and alkalosis, have been vomiting, have used diuretics, or have an inherited renal tubulopathy such as Bartter or Gitelman syndrome. Usually, differentiating Bartter and Gitelman syndromes from chronic vomiting or diuretic use is done with the history and physical examination. However, in patients with a questionable history and a lack of findings on physical examination, checking the urinary chloride, potassium, calcium, and creatinine may be helpful.

A urinary potassium-creatinine ratio greater than 15 suggests renal loss, whereas a ratio less than 15 suggests extrarenal loss.⁹

Patients who are taking a diuretic or who have Bartter or Gitelman syndrome have a high urinary chloride concentration, ie, greater than 20 mmol/L, whereas patients with hypokalemia and alkalosis from chronic vomiting tend to have a concentration less than 10 mmol/L.¹⁰

Table 1 summarizes an approach to the evaluation of unexplained hypokalemia based on blood pressure and acid-base status.

A HIDDEN HISTORY

On further questioning, the patient admits to an 8-year history of daily self-induced vomiting in an attempt to lose weight, in addition to multiple hospitalizations for hypokalemia and a previous diagnosis of an eating disorder.

INITIAL MANAGEMENT OF HYPOKALEMIA

The initial management of hypokalemia should focus on life-threatening emergencies. While patients with potassium levels greater than 3 mmol/L are usually asymptomatic, those with levels below 3 mmol/L present with muscle weakness and rhabdomyolysis.⁴ An acute drop in serum potassium to less than 2 mmol/L is associated with respiratory muscle weakness and ventricular arrhythmias.⁴ If the patient has cardiac symptoms or hypoventilation due to respiratory muscle weakness, continuous monitoring in the intensive care unit and aggressive therapy are warranted.

4. Which potassium formulation is most appropriate for the treatment of hypokalemia in this patient?

• Potassium chloride
• Potassium phosphate
• Potassium acetate

Oral potassium is preferable in patients with a serum potassium above 2.5 mmol/L.^4,11 Potassium phosphate should be used when supplementation with both potassium and phosphorus is needed. Potassium acetate should be reserved for patients with acidosis and hypokalemia. Otherwise, potassium chloride is typically preferred.^4,12 It comes in liquid and tablet forms. Liquid forms have an unpleasant taste, whereas tablets are usually well tolerated. No more than 20 to 40 mEq of potassium chloride tablets should be given at a time, since higher doses are associated with gastrointestinal mucosal injury.¹²

Potassium chloride is particularly preferred in patients with metabolic alkalosis, since increased chloride intake and delivery to the distal tubule increases the expression of pendrin, a luminal chloride and bicarbonate exchanger in the cortical collecting duct.¹³ With metabolic alkalosis, increased excretion of bicarbonate occurs through up-regulation of pendrin. Potassium depletion down-regulates pendrin.¹³ Additionally, correction of metabolic alkalosis increases serum potassium by movement of potassium from the intracellular to the extracellular space.

Intravenous potassium should be reserved for patients with severe hypokalemia (< 2.5 mmol/L) or significant arrhythmias.¹¹ Oral and intravenous potassium can safely be given simultaneously.¹¹ The intravenous rate should not exceed more than 10 to 20 mEq of potassium chloride per hour unless the patient has a life-threatening arrhythmia, respiratory failure, or severe hypokalemia.^14,15 In life-threatening situations, a femoral line should be placed, and potassium should be given as rapidly as 20 mEq over 15 to 20 minutes.¹⁴ Cannulation of the subclavian and internal jugular veins should be avoided in severe hypokalemia since mechanical irritation from guidewire placement can provoke ventricular arrhythmias.¹⁴

During intravenous administration of potassium, laboratory monitoring after every 20 mEq of potassium chloride is advised because of the possibility of rebound hyperkalemia. In patients with severe hypokalemia, avoidance of factors that can worsen intracellular shift of potassium is also important. Avoid dextrose-containing fluids to prevent insulin-induced shifting of potassium into cells. Restore intravascular volume to blunt hypovolemia-induced renin and aldosterone secretion. If a patient presents with severe hypokalemia and acidosis, correct the hypokalemia before the acidosis to avoid intracellular shift of potassium.

OUR PATIENT’S MANAGEMENT AND FOLLOW-UP PLAN

Given the severity of our patient’s hypokalemia and her complaint of palpitations, she was admitted to the hospital for monitoring. She required 180 mEq of intravenous potassium chloride and 140 mEq of oral potassium chloride during the first 24 hours in order to achieve a serum potassium level above 3 mmol/L. Electrocardiographic U waves resolved once the level was above 2 mmol/L, and ST depressions resolved once it was above 3 mmol/L. The QT interval normalized after 24 hours of hospitalization.

On discharge, she was prescribed oral potassium chloride 40 mEq daily and magnesium sulfate 400 mg twice daily, with plans for a followup visit with her outpatient therapy team, which includes a psychiatrist, a social worker, and her primary care provider. She declined a referral for inpatient therapy but agreed to a goal of decreasing the frequency of induced vomiting and outpatient visits. She was also educated on how and when to access emergency medical care.¹⁶

A 20-year-old woman presents to the emergency department with fatigue and the sudden onset of palpitations. She reports no history of significant illness or surgery. She says she is not currently taking prescription or over-the-counter medications. She does not smoke, drink alcohol, or use illicit drugs.

Her weight is 52 kg (115 lb), her height is 170 cm (67 in), and her body mass index (BMI) is 18 kg/m². Vital signs: temperature 35.7°C (96.4°F), blood pressure 92/48 mm Hg, heart rate 73 bpm, respiratory rate 5 breaths per minute, and oxygen saturation 98% on room air.

She appears tired but is alert, conversant, and cooperative. Her skin is normal, and dentition is fair. Her pulse is regular, and respirations are slow. The abdomen is soft, non-tender, and flat. Strength is 4 on a scale of 5 in all extremities. Deep-tendon reflexes are 2+ and symmetric.

Electrocardiography (Figure 1) in the emergency department shows ST-segment depression, a prolonged corrected QT interval of 665 msec, T-wave inversion, PR prolongation, increased P-wave amplitude, and U waves.

1. Which electrolyte abnormality is associated with this electrocardiographic picture?

• Hypercalcemia
• Hyperkalemia
• Hypocalcemia
• Hypokalemia

Hypokalemia is the likely cause of these findings. The finding of U waves is considered significant when they are inverted, merged with the T wave, or have an amplitude greater than the T wave.¹ U waves are best seen in the precordial leads. When severe, hypokalemia can lead to potentially fatal arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, and ventricular fibrillation.²

Hyperkalemia is associated with peaked T waves, a prolonged PR interval, decreased P wave amplitude, and a widened QRS complex.² When acute and severe, hyperkalemia is associated with ventricular arrhythmia.

Hypocalcemia is associated with a prolonged QT interval and ventricular dysrhythmia, but not U waves.²

Hypercalcemia is associated with bradydysrhythmia, as well as with a shortened QT interval.²

LABORATORY TESTING

Laboratory testing shows the following:

• Sodium 126 mmol/L (reference range 135–145)
• Potassium 1.5 mmol/L (3.5–5.1)
• Chloride 58 mmol/L (100–110)
• Bicarbonate 62 mmol/L (20–30)
• Blood urea nitrogen 16 mg/dL (7–18)
• Creatinine 0.8 mg/dL (0.5–1.0)
• Glucose 106 mg/dL (70–110)
• Ionized calcium 4.4 mg/dL (4.5–5.3)
• Magnesium 1.8 mg/dL (1.7–2.3)
• Phosphorus 4.1 mg/dL (2.5–4.5)
• Venous blood gases pH 7.56 (7.35–7.45), Pco₂ 69 mm Hg (35–45).

POTASSIUM HOMEOSTASIS

Ninety-eight percent of potassium is intracellular and only 2% is extracellular.³ The main cellular stores are myocytes and hepatocytes. Patients with decreased muscle mass may be at a higher risk of hypokalemia as a result of decreased skeletal muscle stores.⁴

The acute development of hypokalemia occurs from transcellular shifts. Alkalosis, insulin secretion, and beta-adrenergic stimulation promote the intracellular uptake of potassium. The major hormonal regulator of potassium excretion is aldosterone, which is stimulated by renal hypoperfusion and promotes potassium-ion secretion in the distal convoluted tubule.

Chronic hypokalemia develops in patients with ongoing renal or gastrointestinal potassium loss. If the cause of potassium loss is not elucidated by the history, the physical, and a review of medications, then one of two things is possible: either the patient has renal tubular disease affecting acid-base and potassium regulation, causing excessive mineralocorticoid secretion, which is associated with an abnormal response to aldosterone; or the patient is not being forthcoming in the history.

2. Which is the most likely cause of hypokalemia in this patient?

• Vomiting
• Liddle syndrome
• Bartter syndrome
• Gitelman syndrome
• Diuretic use

Her laboratory tests reveal hypokalemia and hyponatremic-hypochloremic metabolic alkalosis with compensatory respiratory acidosis. In metabolic alkalosis, the expected respiratory compensation is an increase of 0.7 mm Hg in Pco₂ for each 1-mEq/L increase in bicarbonate. Therefore, the expected Pco₂ is 67, close to the patient’s actual value of 69.

Protracted vomiting with loss of gastric acid juices could be a cause of the metabolic disturbances in this young woman, although she did not mention vomiting during the history.

Liddle syndrome, or pseudoaldosteronism, is a rare autosomal dominant disorder characterized by altered renal epithelial sodium channels, excessive sodium retention, and resultant hypertension. Hypokalemia and alkalosis are seen in Liddle syndrome, but the absence of hypertension in our patient makes Liddle syndrome unlikely.

Bartter syndrome is an inherited autosomal recessive disorder of the sodium-potassium-chloride cotransporter in the thick ascending loop of Henle, resulting in impaired reabsorption of chloride and sodium. Bartter syndrome mimics chronic loop-diuretic use and is associated with hypercalciuria. Bartter syndrome is possible in this patient; however, patients with Bartter syndrome are usually diagnosed in infancy or childhood and have evidence of growth impairment.

Gitelman syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride cotransporter. Although Gitelman syndrome is more common than Bartter syndrome and presents at older ages, it is not usually associated with such profound metabolic alkalosis. Gitelman syndrome mimics chronic use of thiazide diuretics and is associated with hypocalciuria.

Diuretic use could also cause the metabolic disturbances described; however, the patient denied taking diuretics.

The most common cause of hypokalemia in clinical practice is diuretic use.⁴ In this young woman with unexplained hypokalemia, the most likely cause is either undisclosed self-induced vomiting or diuretic abuse. The degree of metabolic alkalosis suggests vomiting, since metabolic alkalosis this severe is usually seen only with protracted vomiting. Bartter and Gitelman syndromes are included in the differential diagnosis, but they are much less common than hypokalemia associated with diuretics or self-induced vomiting.⁵

3. Which test could help elucidate the cause of hypokalemia in this patient?

• Ratio of plasma aldosterone to rennin
• Urine chloride
• Ratio of urinary potassium to creatinine
• Urinary anion gap and urinary pH

APPROACH TO HYPOKALEMIA

Determining the cause of hypokalemia starts with a thorough history and physical examination. The history should focus on drugs such as diuretics and laxatives. Women should be asked about their menstrual history since irregular periods may suggest an eating disorder. The physical examination should focus on signs that suggest self-induced vomiting, such as dry skin, dental erosions, enlarged parotid glands, and calluses or scars on the knuckles.

Patients with an unclear cause of hypokalemia after a thorough history and physical examination can be categorized into one of three groups based on blood pressure and acid-base status:

• Hypokalemia, hypertension, metabolic alkalosis
• Hypokalemia, normal blood pressure, metabolic acidosis
• Hypokalemia, normal blood pressure, metabolic alkalosis.

Hypokalemia, hypertension, metabolic alkalosis

The blood pressure provides an important clue in the evaluation of hypokalemia. The combination of hypertension, hypokalemia, and alkalosis should raise concern for hyperaldosteronism or pseudoaldosteronism. Primary hyperaldosteronism from an adrenal adenoma (Conn syndrome) is characterized by a plasma aldosterone-renin ratio of greater than 20.^6,7 In contrast, patients with secondary hyperaldosteronism due to renovascular disease have a plasma aldosterone-renin ratio of less than 10. Patients with pseudoaldosteronism have low aldosterone and renin levels and hypertension. Since our patient has a normal blood pressure, testing the plasma aldosterone and renin levels would not help determine the cause of her hypokalemia.

Hypokalemia, normal blood pressure, metabolic acidosis

Patients with normal blood pressure, hypokalemia, and normal plasma anion gap acidosis either have renal tubular acidosis or have lost potassium because of diarrhea or laxative abuse. In a patient who denies taking laxatives or denies a history of diarrhea, checking the urinary anion gap and urinary pH may help differentiate the cause of acidosis and hypokalemia.

The urinary anion gap, calculated by the equation sodium + potassium − chloride, is an indirect estimate of hydrogen excretion in the form of ammonium ion⁸; the normal value is 0 to 10 mEq/L. A negative value represents increased hydrogen excretion in response to systemic acidosis from gastrointestinal or renal loss of bicarbonate (proximal renal tubular acidosis). A urinary pH greater than 5.5 in the setting of systemic acidosis suggests impaired ability of the kidneys to acidify urine and raises the possibility of renal tubular acidosis.

This patient has metabolic alkalosis, so calculation of the urinary anion gap would not be helpful.

Hypokalemia, normal blood pressure, metabolic alkalosis

Patients such as ours, with normal blood pressure, hypokalemia, and alkalosis, have been vomiting, have used diuretics, or have an inherited renal tubulopathy such as Bartter or Gitelman syndrome. Usually, differentiating Bartter and Gitelman syndromes from chronic vomiting or diuretic use is done with the history and physical examination. However, in patients with a questionable history and a lack of findings on physical examination, checking the urinary chloride, potassium, calcium, and creatinine may be helpful.

A urinary potassium-creatinine ratio greater than 15 suggests renal loss, whereas a ratio less than 15 suggests extrarenal loss.⁹

Patients who are taking a diuretic or who have Bartter or Gitelman syndrome have a high urinary chloride concentration, ie, greater than 20 mmol/L, whereas patients with hypokalemia and alkalosis from chronic vomiting tend to have a concentration less than 10 mmol/L.¹⁰

Table 1 summarizes an approach to the evaluation of unexplained hypokalemia based on blood pressure and acid-base status.

A HIDDEN HISTORY

On further questioning, the patient admits to an 8-year history of daily self-induced vomiting in an attempt to lose weight, in addition to multiple hospitalizations for hypokalemia and a previous diagnosis of an eating disorder.

INITIAL MANAGEMENT OF HYPOKALEMIA

The initial management of hypokalemia should focus on life-threatening emergencies. While patients with potassium levels greater than 3 mmol/L are usually asymptomatic, those with levels below 3 mmol/L present with muscle weakness and rhabdomyolysis.⁴ An acute drop in serum potassium to less than 2 mmol/L is associated with respiratory muscle weakness and ventricular arrhythmias.⁴ If the patient has cardiac symptoms or hypoventilation due to respiratory muscle weakness, continuous monitoring in the intensive care unit and aggressive therapy are warranted.

4. Which potassium formulation is most appropriate for the treatment of hypokalemia in this patient?

• Potassium chloride
• Potassium phosphate
• Potassium acetate

Oral potassium is preferable in patients with a serum potassium above 2.5 mmol/L.^4,11 Potassium phosphate should be used when supplementation with both potassium and phosphorus is needed. Potassium acetate should be reserved for patients with acidosis and hypokalemia. Otherwise, potassium chloride is typically preferred.^4,12 It comes in liquid and tablet forms. Liquid forms have an unpleasant taste, whereas tablets are usually well tolerated. No more than 20 to 40 mEq of potassium chloride tablets should be given at a time, since higher doses are associated with gastrointestinal mucosal injury.¹²

Potassium chloride is particularly preferred in patients with metabolic alkalosis, since increased chloride intake and delivery to the distal tubule increases the expression of pendrin, a luminal chloride and bicarbonate exchanger in the cortical collecting duct.¹³ With metabolic alkalosis, increased excretion of bicarbonate occurs through up-regulation of pendrin. Potassium depletion down-regulates pendrin.¹³ Additionally, correction of metabolic alkalosis increases serum potassium by movement of potassium from the intracellular to the extracellular space.

Intravenous potassium should be reserved for patients with severe hypokalemia (< 2.5 mmol/L) or significant arrhythmias.¹¹ Oral and intravenous potassium can safely be given simultaneously.¹¹ The intravenous rate should not exceed more than 10 to 20 mEq of potassium chloride per hour unless the patient has a life-threatening arrhythmia, respiratory failure, or severe hypokalemia.^14,15 In life-threatening situations, a femoral line should be placed, and potassium should be given as rapidly as 20 mEq over 15 to 20 minutes.¹⁴ Cannulation of the subclavian and internal jugular veins should be avoided in severe hypokalemia since mechanical irritation from guidewire placement can provoke ventricular arrhythmias.¹⁴

During intravenous administration of potassium, laboratory monitoring after every 20 mEq of potassium chloride is advised because of the possibility of rebound hyperkalemia. In patients with severe hypokalemia, avoidance of factors that can worsen intracellular shift of potassium is also important. Avoid dextrose-containing fluids to prevent insulin-induced shifting of potassium into cells. Restore intravascular volume to blunt hypovolemia-induced renin and aldosterone secretion. If a patient presents with severe hypokalemia and acidosis, correct the hypokalemia before the acidosis to avoid intracellular shift of potassium.

OUR PATIENT’S MANAGEMENT AND FOLLOW-UP PLAN

Given the severity of our patient’s hypokalemia and her complaint of palpitations, she was admitted to the hospital for monitoring. She required 180 mEq of intravenous potassium chloride and 140 mEq of oral potassium chloride during the first 24 hours in order to achieve a serum potassium level above 3 mmol/L. Electrocardiographic U waves resolved once the level was above 2 mmol/L, and ST depressions resolved once it was above 3 mmol/L. The QT interval normalized after 24 hours of hospitalization.

On discharge, she was prescribed oral potassium chloride 40 mEq daily and magnesium sulfate 400 mg twice daily, with plans for a followup visit with her outpatient therapy team, which includes a psychiatrist, a social worker, and her primary care provider. She declined a referral for inpatient therapy but agreed to a goal of decreasing the frequency of induced vomiting and outpatient visits. She was also educated on how and when to access emergency medical care.¹⁶

A 20-year-old woman presents to the emergency department with fatigue and the sudden onset of palpitations. She reports no history of significant illness or surgery. She says she is not currently taking prescription or over-the-counter medications. She does not smoke, drink alcohol, or use illicit drugs.

Her weight is 52 kg (115 lb), her height is 170 cm (67 in), and her body mass index (BMI) is 18 kg/m². Vital signs: temperature 35.7°C (96.4°F), blood pressure 92/48 mm Hg, heart rate 73 bpm, respiratory rate 5 breaths per minute, and oxygen saturation 98% on room air.

She appears tired but is alert, conversant, and cooperative. Her skin is normal, and dentition is fair. Her pulse is regular, and respirations are slow. The abdomen is soft, non-tender, and flat. Strength is 4 on a scale of 5 in all extremities. Deep-tendon reflexes are 2+ and symmetric.

Electrocardiography (Figure 1) in the emergency department shows ST-segment depression, a prolonged corrected QT interval of 665 msec, T-wave inversion, PR prolongation, increased P-wave amplitude, and U waves.

1. Which electrolyte abnormality is associated with this electrocardiographic picture?

• Hypercalcemia
• Hyperkalemia
• Hypocalcemia
• Hypokalemia

Hypokalemia is the likely cause of these findings. The finding of U waves is considered significant when they are inverted, merged with the T wave, or have an amplitude greater than the T wave.¹ U waves are best seen in the precordial leads. When severe, hypokalemia can lead to potentially fatal arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, and ventricular fibrillation.²

Hyperkalemia is associated with peaked T waves, a prolonged PR interval, decreased P wave amplitude, and a widened QRS complex.² When acute and severe, hyperkalemia is associated with ventricular arrhythmia.

Hypocalcemia is associated with a prolonged QT interval and ventricular dysrhythmia, but not U waves.²

Hypercalcemia is associated with bradydysrhythmia, as well as with a shortened QT interval.²

LABORATORY TESTING

Laboratory testing shows the following:

• Sodium 126 mmol/L (reference range 135–145)
• Potassium 1.5 mmol/L (3.5–5.1)
• Chloride 58 mmol/L (100–110)
• Bicarbonate 62 mmol/L (20–30)
• Blood urea nitrogen 16 mg/dL (7–18)
• Creatinine 0.8 mg/dL (0.5–1.0)
• Glucose 106 mg/dL (70–110)
• Ionized calcium 4.4 mg/dL (4.5–5.3)
• Magnesium 1.8 mg/dL (1.7–2.3)
• Phosphorus 4.1 mg/dL (2.5–4.5)
• Venous blood gases pH 7.56 (7.35–7.45), Pco₂ 69 mm Hg (35–45).

POTASSIUM HOMEOSTASIS

Ninety-eight percent of potassium is intracellular and only 2% is extracellular.³ The main cellular stores are myocytes and hepatocytes. Patients with decreased muscle mass may be at a higher risk of hypokalemia as a result of decreased skeletal muscle stores.⁴

The acute development of hypokalemia occurs from transcellular shifts. Alkalosis, insulin secretion, and beta-adrenergic stimulation promote the intracellular uptake of potassium. The major hormonal regulator of potassium excretion is aldosterone, which is stimulated by renal hypoperfusion and promotes potassium-ion secretion in the distal convoluted tubule.

Chronic hypokalemia develops in patients with ongoing renal or gastrointestinal potassium loss. If the cause of potassium loss is not elucidated by the history, the physical, and a review of medications, then one of two things is possible: either the patient has renal tubular disease affecting acid-base and potassium regulation, causing excessive mineralocorticoid secretion, which is associated with an abnormal response to aldosterone; or the patient is not being forthcoming in the history.

2. Which is the most likely cause of hypokalemia in this patient?

• Vomiting
• Liddle syndrome
• Bartter syndrome
• Gitelman syndrome
• Diuretic use

Her laboratory tests reveal hypokalemia and hyponatremic-hypochloremic metabolic alkalosis with compensatory respiratory acidosis. In metabolic alkalosis, the expected respiratory compensation is an increase of 0.7 mm Hg in Pco₂ for each 1-mEq/L increase in bicarbonate. Therefore, the expected Pco₂ is 67, close to the patient’s actual value of 69.

Protracted vomiting with loss of gastric acid juices could be a cause of the metabolic disturbances in this young woman, although she did not mention vomiting during the history.

Liddle syndrome, or pseudoaldosteronism, is a rare autosomal dominant disorder characterized by altered renal epithelial sodium channels, excessive sodium retention, and resultant hypertension. Hypokalemia and alkalosis are seen in Liddle syndrome, but the absence of hypertension in our patient makes Liddle syndrome unlikely.

Bartter syndrome is an inherited autosomal recessive disorder of the sodium-potassium-chloride cotransporter in the thick ascending loop of Henle, resulting in impaired reabsorption of chloride and sodium. Bartter syndrome mimics chronic loop-diuretic use and is associated with hypercalciuria. Bartter syndrome is possible in this patient; however, patients with Bartter syndrome are usually diagnosed in infancy or childhood and have evidence of growth impairment.

Gitelman syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride cotransporter. Although Gitelman syndrome is more common than Bartter syndrome and presents at older ages, it is not usually associated with such profound metabolic alkalosis. Gitelman syndrome mimics chronic use of thiazide diuretics and is associated with hypocalciuria.

Diuretic use could also cause the metabolic disturbances described; however, the patient denied taking diuretics.

The most common cause of hypokalemia in clinical practice is diuretic use.⁴ In this young woman with unexplained hypokalemia, the most likely cause is either undisclosed self-induced vomiting or diuretic abuse. The degree of metabolic alkalosis suggests vomiting, since metabolic alkalosis this severe is usually seen only with protracted vomiting. Bartter and Gitelman syndromes are included in the differential diagnosis, but they are much less common than hypokalemia associated with diuretics or self-induced vomiting.⁵

3. Which test could help elucidate the cause of hypokalemia in this patient?

• Ratio of plasma aldosterone to rennin
• Urine chloride
• Ratio of urinary potassium to creatinine
• Urinary anion gap and urinary pH

APPROACH TO HYPOKALEMIA

Determining the cause of hypokalemia starts with a thorough history and physical examination. The history should focus on drugs such as diuretics and laxatives. Women should be asked about their menstrual history since irregular periods may suggest an eating disorder. The physical examination should focus on signs that suggest self-induced vomiting, such as dry skin, dental erosions, enlarged parotid glands, and calluses or scars on the knuckles.

Patients with an unclear cause of hypokalemia after a thorough history and physical examination can be categorized into one of three groups based on blood pressure and acid-base status:

• Hypokalemia, hypertension, metabolic alkalosis
• Hypokalemia, normal blood pressure, metabolic acidosis
• Hypokalemia, normal blood pressure, metabolic alkalosis.

Hypokalemia, hypertension, metabolic alkalosis

The blood pressure provides an important clue in the evaluation of hypokalemia. The combination of hypertension, hypokalemia, and alkalosis should raise concern for hyperaldosteronism or pseudoaldosteronism. Primary hyperaldosteronism from an adrenal adenoma (Conn syndrome) is characterized by a plasma aldosterone-renin ratio of greater than 20.^6,7 In contrast, patients with secondary hyperaldosteronism due to renovascular disease have a plasma aldosterone-renin ratio of less than 10. Patients with pseudoaldosteronism have low aldosterone and renin levels and hypertension. Since our patient has a normal blood pressure, testing the plasma aldosterone and renin levels would not help determine the cause of her hypokalemia.

Hypokalemia, normal blood pressure, metabolic acidosis

Patients with normal blood pressure, hypokalemia, and normal plasma anion gap acidosis either have renal tubular acidosis or have lost potassium because of diarrhea or laxative abuse. In a patient who denies taking laxatives or denies a history of diarrhea, checking the urinary anion gap and urinary pH may help differentiate the cause of acidosis and hypokalemia.

The urinary anion gap, calculated by the equation sodium + potassium − chloride, is an indirect estimate of hydrogen excretion in the form of ammonium ion⁸; the normal value is 0 to 10 mEq/L. A negative value represents increased hydrogen excretion in response to systemic acidosis from gastrointestinal or renal loss of bicarbonate (proximal renal tubular acidosis). A urinary pH greater than 5.5 in the setting of systemic acidosis suggests impaired ability of the kidneys to acidify urine and raises the possibility of renal tubular acidosis.

This patient has metabolic alkalosis, so calculation of the urinary anion gap would not be helpful.

Hypokalemia, normal blood pressure, metabolic alkalosis

Patients such as ours, with normal blood pressure, hypokalemia, and alkalosis, have been vomiting, have used diuretics, or have an inherited renal tubulopathy such as Bartter or Gitelman syndrome. Usually, differentiating Bartter and Gitelman syndromes from chronic vomiting or diuretic use is done with the history and physical examination. However, in patients with a questionable history and a lack of findings on physical examination, checking the urinary chloride, potassium, calcium, and creatinine may be helpful.

A urinary potassium-creatinine ratio greater than 15 suggests renal loss, whereas a ratio less than 15 suggests extrarenal loss.⁹

Patients who are taking a diuretic or who have Bartter or Gitelman syndrome have a high urinary chloride concentration, ie, greater than 20 mmol/L, whereas patients with hypokalemia and alkalosis from chronic vomiting tend to have a concentration less than 10 mmol/L.¹⁰

Table 1 summarizes an approach to the evaluation of unexplained hypokalemia based on blood pressure and acid-base status.

A HIDDEN HISTORY

On further questioning, the patient admits to an 8-year history of daily self-induced vomiting in an attempt to lose weight, in addition to multiple hospitalizations for hypokalemia and a previous diagnosis of an eating disorder.

INITIAL MANAGEMENT OF HYPOKALEMIA

The initial management of hypokalemia should focus on life-threatening emergencies. While patients with potassium levels greater than 3 mmol/L are usually asymptomatic, those with levels below 3 mmol/L present with muscle weakness and rhabdomyolysis.⁴ An acute drop in serum potassium to less than 2 mmol/L is associated with respiratory muscle weakness and ventricular arrhythmias.⁴ If the patient has cardiac symptoms or hypoventilation due to respiratory muscle weakness, continuous monitoring in the intensive care unit and aggressive therapy are warranted.

4. Which potassium formulation is most appropriate for the treatment of hypokalemia in this patient?

• Potassium chloride
• Potassium phosphate
• Potassium acetate

Oral potassium is preferable in patients with a serum potassium above 2.5 mmol/L.^4,11 Potassium phosphate should be used when supplementation with both potassium and phosphorus is needed. Potassium acetate should be reserved for patients with acidosis and hypokalemia. Otherwise, potassium chloride is typically preferred.^4,12 It comes in liquid and tablet forms. Liquid forms have an unpleasant taste, whereas tablets are usually well tolerated. No more than 20 to 40 mEq of potassium chloride tablets should be given at a time, since higher doses are associated with gastrointestinal mucosal injury.¹²

Potassium chloride is particularly preferred in patients with metabolic alkalosis, since increased chloride intake and delivery to the distal tubule increases the expression of pendrin, a luminal chloride and bicarbonate exchanger in the cortical collecting duct.¹³ With metabolic alkalosis, increased excretion of bicarbonate occurs through up-regulation of pendrin. Potassium depletion down-regulates pendrin.¹³ Additionally, correction of metabolic alkalosis increases serum potassium by movement of potassium from the intracellular to the extracellular space.

Intravenous potassium should be reserved for patients with severe hypokalemia (< 2.5 mmol/L) or significant arrhythmias.¹¹ Oral and intravenous potassium can safely be given simultaneously.¹¹ The intravenous rate should not exceed more than 10 to 20 mEq of potassium chloride per hour unless the patient has a life-threatening arrhythmia, respiratory failure, or severe hypokalemia.^14,15 In life-threatening situations, a femoral line should be placed, and potassium should be given as rapidly as 20 mEq over 15 to 20 minutes.¹⁴ Cannulation of the subclavian and internal jugular veins should be avoided in severe hypokalemia since mechanical irritation from guidewire placement can provoke ventricular arrhythmias.¹⁴

During intravenous administration of potassium, laboratory monitoring after every 20 mEq of potassium chloride is advised because of the possibility of rebound hyperkalemia. In patients with severe hypokalemia, avoidance of factors that can worsen intracellular shift of potassium is also important. Avoid dextrose-containing fluids to prevent insulin-induced shifting of potassium into cells. Restore intravascular volume to blunt hypovolemia-induced renin and aldosterone secretion. If a patient presents with severe hypokalemia and acidosis, correct the hypokalemia before the acidosis to avoid intracellular shift of potassium.

OUR PATIENT’S MANAGEMENT AND FOLLOW-UP PLAN

Given the severity of our patient’s hypokalemia and her complaint of palpitations, she was admitted to the hospital for monitoring. She required 180 mEq of intravenous potassium chloride and 140 mEq of oral potassium chloride during the first 24 hours in order to achieve a serum potassium level above 3 mmol/L. Electrocardiographic U waves resolved once the level was above 2 mmol/L, and ST depressions resolved once it was above 3 mmol/L. The QT interval normalized after 24 hours of hospitalization.

On discharge, she was prescribed oral potassium chloride 40 mEq daily and magnesium sulfate 400 mg twice daily, with plans for a followup visit with her outpatient therapy team, which includes a psychiatrist, a social worker, and her primary care provider. She declined a referral for inpatient therapy but agreed to a goal of decreasing the frequency of induced vomiting and outpatient visits. She was also educated on how and when to access emergency medical care.¹⁶

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.