SAN DIEGO– A fuller picture of the benefits of vorapaxar for secondary cardiovascular prevention emerged from three separate secondary analyses of the pivotal Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P TIMI-50) trial presented at the annual meeting of the American College of Cardiology.

These new reports provided evidence that vorapaxar (Zontivity), a first-in-class, once-daily thrombin inhibitor with rapid onset and a half-life in excess of 7 days, reduces acute limb ischemia and the need for peripheral revascularization in patients with peripheral arterial disease (PAD), and also that the antiplatelet agent is particularly beneficial in patients with a history of coronary artery bypass graft surgery.

That being said, the three secondary analyses were post hoc and as such are inherently exploratory and hypothesis-generating rather than definitive, the investigators noted.

The Food and Drug Administration approved vorapaxar in May 2014 for the reduction of thrombotic cardiovascular events in patients with a history of MI or in patients with PAD in the absence of a previous stroke or TIA. Marketing approval was based chiefly on the results of the landmark 26,449-patient, double-blind, prospective, multinational TIMI 50 trial. In an analysis of the 20,170 randomized patients without a prior stroke or TIA, vorapaxar at 2.5 mg once daily, when added to standard therapy with aspirin and/or clopidogrel, reduced the 3-year rate of a composite outcome – comprised of cardiovascular death, MI, or stroke – by 20% compared with placebo, with a number-needed-to-treat of 63 (J. Am. Heart Assoc. 2015 [doi: 10.1161/JAHA.114.001505]).

At ACC 15, Dr. Ethan C. Kosova presented a subanalysis involving the 2,942 TIMI 50 participants who had undergone CABG surgery prior to the study. The rationale for taking a closer look at this group is that rates of venous graft occlusion and recurrent ischemic events remain high after CABG surgery, so the efficacy and safety of vorapaxar in this population are of particular interest.

Underscoring the high-risk nature of this population, at baseline the patients with a history of CABG were significantly older and had higher rates of hypertension, dyslipidemia, diabetes, PAD, heart failure, and chronic kidney disease than participants without prior CABG who had no history of stroke or TIA, observed Dr. Kosova of Brigham and Women’s Hospital, Boston.

The 3-year composite event rate of cardiovascular death, MI, or stroke occurred in 11.9% of the 1,471 patients with prior CABG who were randomized to vorapaxar compared with 15.6% of those on placebo. That translates into a 29% relative risk reduction and a number-needed-to-treat of 27, an even stronger result than in the general study population.

Moreover, the clinically relevant composite outcome consisting of cardiovascular death or MI occurred in 10.9% of those on vorapaxar compared with 14.3% of controls, for a 29% relative risk reduction and a number-needed-to-treat of 29, he continued.

The 3-year all-cause mortality was 5.8% in patients with prior CABG who received vorapaxar compared to 8% in those on placebo.

Vorapaxar, which inhibits protease-activated receptor-1 on platelets and vascular endothelium, increased the rate of GUSTO moderate-to-severe bleeding: 6.8% compared with 3.7% in controls.

“Putting together the efficacy and safety data to derive the net clinical outcome – the combined endpoint of all-cause mortality, MI, cerebrovascular accident, and GUSTO severe bleeding – the result was a 28% improvement with vorapaxar compared with placebo,” Dr. Kosova said.

In a separate presentation focused on the 3,787 patients who gained entry into the TIMI 50 trial on the basis of symptomatic PAD, Dr. Antonio Gutierrez reported that acute limb ischemia occurred in 109 of them during the trial. Fifty-four percent of these events were due to acute surgical graft thrombosis, 27% to in situ thrombosis of a native vessel, and lesser numbers were due to thromboembolissm or stent thrombosis.

The 3-year acute limb ischemia rate in patients with baseline PAD was 3.9% with placebo compared to 2.3% with vorapaxar, for a 42% relative risk reduction, according to Dr. Gutierrez of Brigham and Women’s Hospital.

Dr. Ian Gilchrist, also from Brigham and Women’s Hospital, reported that in TIMI 50 participants with a history of PAD, vorapaxar resulted in a 16% reduction in the need for peripheral revascularization procedures for claudication, with rates of 9.4% for vorapaxar and 11.6% for placebo. There was also a statistically significant 41% reduction in the rate of surgical peripheral revascularization procedures, with rates of 4.5% for vorapaxar and 7.7% for placebo.

The TIMI 50 trial was funded by Merck. Drs. Kosova, Gutierrez, and Gilchrist reported having no financial conflicts of interest.

[email protected]

SAN DIEGO– A fuller picture of the benefits of vorapaxar for secondary cardiovascular prevention emerged from three separate secondary analyses of the pivotal Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P TIMI-50) trial presented at the annual meeting of the American College of Cardiology.

These new reports provided evidence that vorapaxar (Zontivity), a first-in-class, once-daily thrombin inhibitor with rapid onset and a half-life in excess of 7 days, reduces acute limb ischemia and the need for peripheral revascularization in patients with peripheral arterial disease (PAD), and also that the antiplatelet agent is particularly beneficial in patients with a history of coronary artery bypass graft surgery.

That being said, the three secondary analyses were post hoc and as such are inherently exploratory and hypothesis-generating rather than definitive, the investigators noted.

The Food and Drug Administration approved vorapaxar in May 2014 for the reduction of thrombotic cardiovascular events in patients with a history of MI or in patients with PAD in the absence of a previous stroke or TIA. Marketing approval was based chiefly on the results of the landmark 26,449-patient, double-blind, prospective, multinational TIMI 50 trial. In an analysis of the 20,170 randomized patients without a prior stroke or TIA, vorapaxar at 2.5 mg once daily, when added to standard therapy with aspirin and/or clopidogrel, reduced the 3-year rate of a composite outcome – comprised of cardiovascular death, MI, or stroke – by 20% compared with placebo, with a number-needed-to-treat of 63 (J. Am. Heart Assoc. 2015 [doi: 10.1161/JAHA.114.001505]).

At ACC 15, Dr. Ethan C. Kosova presented a subanalysis involving the 2,942 TIMI 50 participants who had undergone CABG surgery prior to the study. The rationale for taking a closer look at this group is that rates of venous graft occlusion and recurrent ischemic events remain high after CABG surgery, so the efficacy and safety of vorapaxar in this population are of particular interest.

Underscoring the high-risk nature of this population, at baseline the patients with a history of CABG were significantly older and had higher rates of hypertension, dyslipidemia, diabetes, PAD, heart failure, and chronic kidney disease than participants without prior CABG who had no history of stroke or TIA, observed Dr. Kosova of Brigham and Women’s Hospital, Boston.

The 3-year composite event rate of cardiovascular death, MI, or stroke occurred in 11.9% of the 1,471 patients with prior CABG who were randomized to vorapaxar compared with 15.6% of those on placebo. That translates into a 29% relative risk reduction and a number-needed-to-treat of 27, an even stronger result than in the general study population.

Moreover, the clinically relevant composite outcome consisting of cardiovascular death or MI occurred in 10.9% of those on vorapaxar compared with 14.3% of controls, for a 29% relative risk reduction and a number-needed-to-treat of 29, he continued.

The 3-year all-cause mortality was 5.8% in patients with prior CABG who received vorapaxar compared to 8% in those on placebo.

Vorapaxar, which inhibits protease-activated receptor-1 on platelets and vascular endothelium, increased the rate of GUSTO moderate-to-severe bleeding: 6.8% compared with 3.7% in controls.

“Putting together the efficacy and safety data to derive the net clinical outcome – the combined endpoint of all-cause mortality, MI, cerebrovascular accident, and GUSTO severe bleeding – the result was a 28% improvement with vorapaxar compared with placebo,” Dr. Kosova said.

In a separate presentation focused on the 3,787 patients who gained entry into the TIMI 50 trial on the basis of symptomatic PAD, Dr. Antonio Gutierrez reported that acute limb ischemia occurred in 109 of them during the trial. Fifty-four percent of these events were due to acute surgical graft thrombosis, 27% to in situ thrombosis of a native vessel, and lesser numbers were due to thromboembolissm or stent thrombosis.

The 3-year acute limb ischemia rate in patients with baseline PAD was 3.9% with placebo compared to 2.3% with vorapaxar, for a 42% relative risk reduction, according to Dr. Gutierrez of Brigham and Women’s Hospital.

Dr. Ian Gilchrist, also from Brigham and Women’s Hospital, reported that in TIMI 50 participants with a history of PAD, vorapaxar resulted in a 16% reduction in the need for peripheral revascularization procedures for claudication, with rates of 9.4% for vorapaxar and 11.6% for placebo. There was also a statistically significant 41% reduction in the rate of surgical peripheral revascularization procedures, with rates of 4.5% for vorapaxar and 7.7% for placebo.

The TIMI 50 trial was funded by Merck. Drs. Kosova, Gutierrez, and Gilchrist reported having no financial conflicts of interest.

[email protected]

SAN DIEGO– A fuller picture of the benefits of vorapaxar for secondary cardiovascular prevention emerged from three separate secondary analyses of the pivotal Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P TIMI-50) trial presented at the annual meeting of the American College of Cardiology.

These new reports provided evidence that vorapaxar (Zontivity), a first-in-class, once-daily thrombin inhibitor with rapid onset and a half-life in excess of 7 days, reduces acute limb ischemia and the need for peripheral revascularization in patients with peripheral arterial disease (PAD), and also that the antiplatelet agent is particularly beneficial in patients with a history of coronary artery bypass graft surgery.

That being said, the three secondary analyses were post hoc and as such are inherently exploratory and hypothesis-generating rather than definitive, the investigators noted.

The Food and Drug Administration approved vorapaxar in May 2014 for the reduction of thrombotic cardiovascular events in patients with a history of MI or in patients with PAD in the absence of a previous stroke or TIA. Marketing approval was based chiefly on the results of the landmark 26,449-patient, double-blind, prospective, multinational TIMI 50 trial. In an analysis of the 20,170 randomized patients without a prior stroke or TIA, vorapaxar at 2.5 mg once daily, when added to standard therapy with aspirin and/or clopidogrel, reduced the 3-year rate of a composite outcome – comprised of cardiovascular death, MI, or stroke – by 20% compared with placebo, with a number-needed-to-treat of 63 (J. Am. Heart Assoc. 2015 [doi: 10.1161/JAHA.114.001505]).

At ACC 15, Dr. Ethan C. Kosova presented a subanalysis involving the 2,942 TIMI 50 participants who had undergone CABG surgery prior to the study. The rationale for taking a closer look at this group is that rates of venous graft occlusion and recurrent ischemic events remain high after CABG surgery, so the efficacy and safety of vorapaxar in this population are of particular interest.

Underscoring the high-risk nature of this population, at baseline the patients with a history of CABG were significantly older and had higher rates of hypertension, dyslipidemia, diabetes, PAD, heart failure, and chronic kidney disease than participants without prior CABG who had no history of stroke or TIA, observed Dr. Kosova of Brigham and Women’s Hospital, Boston.

The 3-year composite event rate of cardiovascular death, MI, or stroke occurred in 11.9% of the 1,471 patients with prior CABG who were randomized to vorapaxar compared with 15.6% of those on placebo. That translates into a 29% relative risk reduction and a number-needed-to-treat of 27, an even stronger result than in the general study population.

Moreover, the clinically relevant composite outcome consisting of cardiovascular death or MI occurred in 10.9% of those on vorapaxar compared with 14.3% of controls, for a 29% relative risk reduction and a number-needed-to-treat of 29, he continued.

The 3-year all-cause mortality was 5.8% in patients with prior CABG who received vorapaxar compared to 8% in those on placebo.

Vorapaxar, which inhibits protease-activated receptor-1 on platelets and vascular endothelium, increased the rate of GUSTO moderate-to-severe bleeding: 6.8% compared with 3.7% in controls.

“Putting together the efficacy and safety data to derive the net clinical outcome – the combined endpoint of all-cause mortality, MI, cerebrovascular accident, and GUSTO severe bleeding – the result was a 28% improvement with vorapaxar compared with placebo,” Dr. Kosova said.

In a separate presentation focused on the 3,787 patients who gained entry into the TIMI 50 trial on the basis of symptomatic PAD, Dr. Antonio Gutierrez reported that acute limb ischemia occurred in 109 of them during the trial. Fifty-four percent of these events were due to acute surgical graft thrombosis, 27% to in situ thrombosis of a native vessel, and lesser numbers were due to thromboembolissm or stent thrombosis.

The 3-year acute limb ischemia rate in patients with baseline PAD was 3.9% with placebo compared to 2.3% with vorapaxar, for a 42% relative risk reduction, according to Dr. Gutierrez of Brigham and Women’s Hospital.

Dr. Ian Gilchrist, also from Brigham and Women’s Hospital, reported that in TIMI 50 participants with a history of PAD, vorapaxar resulted in a 16% reduction in the need for peripheral revascularization procedures for claudication, with rates of 9.4% for vorapaxar and 11.6% for placebo. There was also a statistically significant 41% reduction in the rate of surgical peripheral revascularization procedures, with rates of 4.5% for vorapaxar and 7.7% for placebo.

The TIMI 50 trial was funded by Merck. Drs. Kosova, Gutierrez, and Gilchrist reported having no financial conflicts of interest.

[email protected]

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has approved the first spray-dried fibrin sealant to help control bleeding during surgery.

The agency approved Raplixa (formerly known as Fibrocaps) for use in adults to control bleeding from small blood vessels when standard surgical techniques are ineffective or impractical.

The standard techniques include suture, ligature, or cautery.

Raplixa contains fibrinogen and thrombin, proteins found in human plasma. When the surgical team applies Raplixa to the bleeding site, the sealant dissolves in the blood, and the fibrinogen and thrombin proteins react, resulting in the formation of blood clots.

The protein components are individually purified using a manufacturing process that includes virus inactivation and removal steps to help reduce the risk for the transmission of blood-borne viruses. The fibrin sealant components are then spray-dried, blended, and packaged in a vial.

Raplixa can be applied directly from the original product vial or by spraying it with a delivery device. Raplixa is used in conjunction with an absorbable gelatin sponge.

“The spray-drying process used to manufacture Raplixa produces dried powders that can be combined into a single vial,” said Karen Midthun, MD, of the FDA’s Center for Biologics Evaluation and Research.

“This eliminates the need to combine the fibrinogen and thrombin before use and allows the product to be stored at room temperature.”

Raplixa was approved for use in the European Union in March, based on the recommendation of the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Phase 3 trial

The FDA approved Raplixa based on data from the FINISH-3 trial, a  randomized, single-blind, controlled, phase 3 study of 719 patients undergoing spinal surgery (n=183), hepatic resection (n=180), vascular surgery (n=175), or soft tissue dissection (n=181) in 4 countries over 11 months.

As reported in the Journal of the American College of Surgeons, adults with mild or moderate surgical bleeding were randomized to recieve Raplixa or the gelatin sponge. Researchers recorded the time to hemostasis over 5 minutes within each surgical indication.

Four hundred and eighty patients were treated with Raplixa, and 239 were treated with the gelatin sponge. Surgeons used the spray device in 53% of Raplixa procedures.

Raplixa used in conjunction with the gelatin sponge significantly reduced time to hemostasis compared to the gelatin sponge alone (P<0.001 for each of the 4 sugical indications).

Raplixa also significantly reduced median time to hemostasis for each indication (P<0.0001).

Adverse events were similar between the treatment arms. The most commonly reported adverse reactions were surgical pain, nausea, constipation, fever, and decreased blood pressure.

Two percent of Raplixa-treated patients developed non-neutralizing anti-thrombin antibodies, as did 3% of patients treated with the gelatin sponge.

Raplixa is manufactured by ProFibrix BV, a wholly owned subsidiary of The Medicines Company, based in Parsippany, New Jersey.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has approved the first spray-dried fibrin sealant to help control bleeding during surgery.

The agency approved Raplixa (formerly known as Fibrocaps) for use in adults to control bleeding from small blood vessels when standard surgical techniques are ineffective or impractical.

The standard techniques include suture, ligature, or cautery.

Raplixa contains fibrinogen and thrombin, proteins found in human plasma. When the surgical team applies Raplixa to the bleeding site, the sealant dissolves in the blood, and the fibrinogen and thrombin proteins react, resulting in the formation of blood clots.

The protein components are individually purified using a manufacturing process that includes virus inactivation and removal steps to help reduce the risk for the transmission of blood-borne viruses. The fibrin sealant components are then spray-dried, blended, and packaged in a vial.

Raplixa can be applied directly from the original product vial or by spraying it with a delivery device. Raplixa is used in conjunction with an absorbable gelatin sponge.

“The spray-drying process used to manufacture Raplixa produces dried powders that can be combined into a single vial,” said Karen Midthun, MD, of the FDA’s Center for Biologics Evaluation and Research.

“This eliminates the need to combine the fibrinogen and thrombin before use and allows the product to be stored at room temperature.”

Raplixa was approved for use in the European Union in March, based on the recommendation of the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Phase 3 trial

The FDA approved Raplixa based on data from the FINISH-3 trial, a  randomized, single-blind, controlled, phase 3 study of 719 patients undergoing spinal surgery (n=183), hepatic resection (n=180), vascular surgery (n=175), or soft tissue dissection (n=181) in 4 countries over 11 months.

As reported in the Journal of the American College of Surgeons, adults with mild or moderate surgical bleeding were randomized to recieve Raplixa or the gelatin sponge. Researchers recorded the time to hemostasis over 5 minutes within each surgical indication.

Four hundred and eighty patients were treated with Raplixa, and 239 were treated with the gelatin sponge. Surgeons used the spray device in 53% of Raplixa procedures.

Raplixa used in conjunction with the gelatin sponge significantly reduced time to hemostasis compared to the gelatin sponge alone (P<0.001 for each of the 4 sugical indications).

Raplixa also significantly reduced median time to hemostasis for each indication (P<0.0001).

Adverse events were similar between the treatment arms. The most commonly reported adverse reactions were surgical pain, nausea, constipation, fever, and decreased blood pressure.

Two percent of Raplixa-treated patients developed non-neutralizing anti-thrombin antibodies, as did 3% of patients treated with the gelatin sponge.

Raplixa is manufactured by ProFibrix BV, a wholly owned subsidiary of The Medicines Company, based in Parsippany, New Jersey.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has approved the first spray-dried fibrin sealant to help control bleeding during surgery.

The agency approved Raplixa (formerly known as Fibrocaps) for use in adults to control bleeding from small blood vessels when standard surgical techniques are ineffective or impractical.

The standard techniques include suture, ligature, or cautery.

Raplixa contains fibrinogen and thrombin, proteins found in human plasma. When the surgical team applies Raplixa to the bleeding site, the sealant dissolves in the blood, and the fibrinogen and thrombin proteins react, resulting in the formation of blood clots.

The protein components are individually purified using a manufacturing process that includes virus inactivation and removal steps to help reduce the risk for the transmission of blood-borne viruses. The fibrin sealant components are then spray-dried, blended, and packaged in a vial.

Raplixa can be applied directly from the original product vial or by spraying it with a delivery device. Raplixa is used in conjunction with an absorbable gelatin sponge.

“The spray-drying process used to manufacture Raplixa produces dried powders that can be combined into a single vial,” said Karen Midthun, MD, of the FDA’s Center for Biologics Evaluation and Research.

“This eliminates the need to combine the fibrinogen and thrombin before use and allows the product to be stored at room temperature.”

Raplixa was approved for use in the European Union in March, based on the recommendation of the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Phase 3 trial

The FDA approved Raplixa based on data from the FINISH-3 trial, a  randomized, single-blind, controlled, phase 3 study of 719 patients undergoing spinal surgery (n=183), hepatic resection (n=180), vascular surgery (n=175), or soft tissue dissection (n=181) in 4 countries over 11 months.

As reported in the Journal of the American College of Surgeons, adults with mild or moderate surgical bleeding were randomized to recieve Raplixa or the gelatin sponge. Researchers recorded the time to hemostasis over 5 minutes within each surgical indication.

Four hundred and eighty patients were treated with Raplixa, and 239 were treated with the gelatin sponge. Surgeons used the spray device in 53% of Raplixa procedures.

Raplixa used in conjunction with the gelatin sponge significantly reduced time to hemostasis compared to the gelatin sponge alone (P<0.001 for each of the 4 sugical indications).

Raplixa also significantly reduced median time to hemostasis for each indication (P<0.0001).

Adverse events were similar between the treatment arms. The most commonly reported adverse reactions were surgical pain, nausea, constipation, fever, and decreased blood pressure.

Two percent of Raplixa-treated patients developed non-neutralizing anti-thrombin antibodies, as did 3% of patients treated with the gelatin sponge.

Raplixa is manufactured by ProFibrix BV, a wholly owned subsidiary of The Medicines Company, based in Parsippany, New Jersey.

Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9197,9196,9195,9194,9193,9192,9191,9190,9189,9188,9187,9186,9185,9184,9183,9182,9181,9180,9179,9178,9177,9176,9175,9171"]

Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9197,9196,9195,9194,9193,9192,9191,9190,9189,9188,9187,9186,9185,9184,9183,9182,9181,9180,9179,9178,9177,9176,9175,9171"]

Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9197,9196,9195,9194,9193,9192,9191,9190,9189,9188,9187,9186,9185,9184,9183,9182,9181,9180,9179,9178,9177,9176,9175,9171"]

Excerpts from our interview with Team Hospitalist member David Weidig, MD, director of hospital medicine for Aurora Medical Group in West Allis, Wis., about best practices for multi-site hospital medicine.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/05/David-Weidig_HM15_FINAL_050215.mp3"][/audio]

Excerpts from our interview with Team Hospitalist member David Weidig, MD, director of hospital medicine for Aurora Medical Group in West Allis, Wis., about best practices for multi-site hospital medicine.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/05/David-Weidig_HM15_FINAL_050215.mp3"][/audio]

Excerpts from our interview with Team Hospitalist member David Weidig, MD, director of hospital medicine for Aurora Medical Group in West Allis, Wis., about best practices for multi-site hospital medicine.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/05/David-Weidig_HM15_FINAL_050215.mp3"][/audio]

SHM founder Win Whitcomb, MD, MHM, chief medical officer of Remedy Partners of Darien, Conn., talks about the annual practice management pre-course in an ever-changing healthcare landscape.

SHM founder Win Whitcomb, MD, MHM, chief medical officer of Remedy Partners of Darien, Conn., talks about the annual practice management pre-course in an ever-changing healthcare landscape.

SHM founder Win Whitcomb, MD, MHM, chief medical officer of Remedy Partners of Darien, Conn., talks about the annual practice management pre-course in an ever-changing healthcare landscape.

In the United States, the cosmetic use of botulinum toxin type A (BTX-A) has continued to grow over the last 15 years, according to multispecialty data recently released by the American Society for Aesthetic Plastic Surgery. During these years, many of our patients, if not ourselves, have undergone treatment faithfully every 3 to 6 months to combat the signs of aging. Subsequently, with the monitoring of adverse events (AEs), the US Food and Drug Administration has issued a black box warning that covers serious side effects—respiratory compromise and death—associated with treatment, yet most of what is listed in the black box warning pertains to medical use rather than cosmetic use. However, with the ever-growing indications for BTX-A, we must be cognizant of the fact that our patients may be receiving concomitant treatment with BTX-A for medical conditions (eg, migraines, hyperhidrosis, achalasia, dysphonia, dystonia, strabismus) by other specialists. Thus, there is a need to understand the potential side effects associated with BTX-A treatments and long-term consequences.

In a January 21 article published online in Pharmacology Yiannakopoulou looked at national monitoring programs through the US Food and Drug Administration and the Danish Medicines Agency. Many of the AEs reported were related to medical use of BTX-A, including anaphylaxis, death, generalized weakness, and dysphagia. Serious AEs related to the cosmetic use of BTX-A included thyroid eye disease, sarcoidal granuloma, pseudoaneurysm of the frontal branch of the superior temporal artery, and severe respiratory failure. Additionally, a patient receiving BTX-A for palmar and axillary hyperhidrosis developed botulinumlike generalized weakness. Upon review of epidemiological studies, the incidence and types of AEs were covered. The vast majority of these events were related to the medical use of BTX-A, which could stem from the lack of long-term studies on cosmetic patients and the lack of reporting of many AEs. The author summarized that minimizing potential AEs relies on proper injection technique, proper storage of the medication, proper dosing, and thorough knowledge of the anatomy.

What’s the issue?

Botulinum toxin type A remains one of the most gratifying treatments for both physicians and patients alike. However, with the potential for abuse, as in the case of the recent fake Botox Cosmetic that has shown up on the market in the United States), we must remain vigilant for AEs. Furthermore, we must continue to emphasize to patients that it is a medical treatment and deserves all the attention and respect we give to other medical interventions. However, as the Yiannakopoulou review has shown, proper injection techniques have a low rate of AEs in the cosmetic use of BTX-A. Have you seen an increase in the number of cosmetic BTX-A patients receiving concomitant treatments with BTX-A for medical conditions? If so, how do you manage them?

We want to know your views! Tell us what you think.

In the United States, the cosmetic use of botulinum toxin type A (BTX-A) has continued to grow over the last 15 years, according to multispecialty data recently released by the American Society for Aesthetic Plastic Surgery. During these years, many of our patients, if not ourselves, have undergone treatment faithfully every 3 to 6 months to combat the signs of aging. Subsequently, with the monitoring of adverse events (AEs), the US Food and Drug Administration has issued a black box warning that covers serious side effects—respiratory compromise and death—associated with treatment, yet most of what is listed in the black box warning pertains to medical use rather than cosmetic use. However, with the ever-growing indications for BTX-A, we must be cognizant of the fact that our patients may be receiving concomitant treatment with BTX-A for medical conditions (eg, migraines, hyperhidrosis, achalasia, dysphonia, dystonia, strabismus) by other specialists. Thus, there is a need to understand the potential side effects associated with BTX-A treatments and long-term consequences.

In a January 21 article published online in Pharmacology Yiannakopoulou looked at national monitoring programs through the US Food and Drug Administration and the Danish Medicines Agency. Many of the AEs reported were related to medical use of BTX-A, including anaphylaxis, death, generalized weakness, and dysphagia. Serious AEs related to the cosmetic use of BTX-A included thyroid eye disease, sarcoidal granuloma, pseudoaneurysm of the frontal branch of the superior temporal artery, and severe respiratory failure. Additionally, a patient receiving BTX-A for palmar and axillary hyperhidrosis developed botulinumlike generalized weakness. Upon review of epidemiological studies, the incidence and types of AEs were covered. The vast majority of these events were related to the medical use of BTX-A, which could stem from the lack of long-term studies on cosmetic patients and the lack of reporting of many AEs. The author summarized that minimizing potential AEs relies on proper injection technique, proper storage of the medication, proper dosing, and thorough knowledge of the anatomy.

What’s the issue?

Botulinum toxin type A remains one of the most gratifying treatments for both physicians and patients alike. However, with the potential for abuse, as in the case of the recent fake Botox Cosmetic that has shown up on the market in the United States), we must remain vigilant for AEs. Furthermore, we must continue to emphasize to patients that it is a medical treatment and deserves all the attention and respect we give to other medical interventions. However, as the Yiannakopoulou review has shown, proper injection techniques have a low rate of AEs in the cosmetic use of BTX-A. Have you seen an increase in the number of cosmetic BTX-A patients receiving concomitant treatments with BTX-A for medical conditions? If so, how do you manage them?

We want to know your views! Tell us what you think.

In the United States, the cosmetic use of botulinum toxin type A (BTX-A) has continued to grow over the last 15 years, according to multispecialty data recently released by the American Society for Aesthetic Plastic Surgery. During these years, many of our patients, if not ourselves, have undergone treatment faithfully every 3 to 6 months to combat the signs of aging. Subsequently, with the monitoring of adverse events (AEs), the US Food and Drug Administration has issued a black box warning that covers serious side effects—respiratory compromise and death—associated with treatment, yet most of what is listed in the black box warning pertains to medical use rather than cosmetic use. However, with the ever-growing indications for BTX-A, we must be cognizant of the fact that our patients may be receiving concomitant treatment with BTX-A for medical conditions (eg, migraines, hyperhidrosis, achalasia, dysphonia, dystonia, strabismus) by other specialists. Thus, there is a need to understand the potential side effects associated with BTX-A treatments and long-term consequences.

In a January 21 article published online in Pharmacology Yiannakopoulou looked at national monitoring programs through the US Food and Drug Administration and the Danish Medicines Agency. Many of the AEs reported were related to medical use of BTX-A, including anaphylaxis, death, generalized weakness, and dysphagia. Serious AEs related to the cosmetic use of BTX-A included thyroid eye disease, sarcoidal granuloma, pseudoaneurysm of the frontal branch of the superior temporal artery, and severe respiratory failure. Additionally, a patient receiving BTX-A for palmar and axillary hyperhidrosis developed botulinumlike generalized weakness. Upon review of epidemiological studies, the incidence and types of AEs were covered. The vast majority of these events were related to the medical use of BTX-A, which could stem from the lack of long-term studies on cosmetic patients and the lack of reporting of many AEs. The author summarized that minimizing potential AEs relies on proper injection technique, proper storage of the medication, proper dosing, and thorough knowledge of the anatomy.

What’s the issue?

Botulinum toxin type A remains one of the most gratifying treatments for both physicians and patients alike. However, with the potential for abuse, as in the case of the recent fake Botox Cosmetic that has shown up on the market in the United States), we must remain vigilant for AEs. Furthermore, we must continue to emphasize to patients that it is a medical treatment and deserves all the attention and respect we give to other medical interventions. However, as the Yiannakopoulou review has shown, proper injection techniques have a low rate of AEs in the cosmetic use of BTX-A. Have you seen an increase in the number of cosmetic BTX-A patients receiving concomitant treatments with BTX-A for medical conditions? If so, how do you manage them?

We want to know your views! Tell us what you think.

New SHM President Robert Harrington Jr., MD, SFHM, talks about his views on hospital medicine, the society and the value of diversity and teamwork.

New SHM President Robert Harrington Jr., MD, SFHM, talks about his views on hospital medicine, the society and the value of diversity and teamwork.

New SHM President Robert Harrington Jr., MD, SFHM, talks about his views on hospital medicine, the society and the value of diversity and teamwork.

ASHEVILLE, N.C. – Recent advances in basic science have shown how the local immune environment in tissue surrounding nonmelanoma skin cancer compares to adjacent normal tissue.

New Mexico Health Sciences Center’s Dr. Andrew Ondo reviewed the latest research in an interview at the annual meeting of the Noah Worcester Dermatological Society. “Each step along the way is a possible target for the treatment of squamous cell carcinoma,” said Dr. Ondo, who indicated that he had no financial conflicts to disclose.

[email protected]

ASHEVILLE, N.C. – Recent advances in basic science have shown how the local immune environment in tissue surrounding nonmelanoma skin cancer compares to adjacent normal tissue.

New Mexico Health Sciences Center’s Dr. Andrew Ondo reviewed the latest research in an interview at the annual meeting of the Noah Worcester Dermatological Society. “Each step along the way is a possible target for the treatment of squamous cell carcinoma,” said Dr. Ondo, who indicated that he had no financial conflicts to disclose.

[email protected]

ASHEVILLE, N.C. – Recent advances in basic science have shown how the local immune environment in tissue surrounding nonmelanoma skin cancer compares to adjacent normal tissue.

New Mexico Health Sciences Center’s Dr. Andrew Ondo reviewed the latest research in an interview at the annual meeting of the Noah Worcester Dermatological Society. “Each step along the way is a possible target for the treatment of squamous cell carcinoma,” said Dr. Ondo, who indicated that he had no financial conflicts to disclose.

[email protected]

The results of the 2015 National Residency Match Program were announced on March 20. For family medicine, the glass was either half empty or half full, depending on your point of view.

On the plus side, 84 more family medicine positions were offered compared to 2014 (3216 vs 3132) and 60 more positions were filled, for a total of 3060 new family medicine residents in 2015.¹ This was far more than matched in gloomy 2009, when only 2555 residents chose family medicine. On the negative side of the balance sheet, there will be 233 fewer family medicine residents this year than matched at the peak of medical student interest in family medicine in 1998.

I’m a glass half full kind of guy, so I am delighted that the trend of increased medical student interest in family medicine continues. According to Merritt Hawkins, a national recruitment firm, family medicine has been the top recruited specialty for several years. The firm reports that starting salaries for family physicians increased by nearly 12% from 2010/11 to 2013/14, which was a higher rate than that of most other specialties.² So there is reason to be optimistic about the future of our specialty.

Our monthly 5-question online quiz can help residents study for their certification exam.

However, to be card-carrying family physicians, our new residents must take the American Board of Family Medicine certification exam, and not all pass on their first attempt. A 2013 study of family medicine residency graduates found that only 86% of graduates passed the board exam on their first try.³

We can help. In addition to the evidence-based reviews published in The Journal of Family Practice (JFP), we have launched a new feature called Residents’ Rapid Review (RRR) to provide an additional resource for residents.

RRR is a monthly 5-question evidence-based quiz prepared by primary care faculty, including current and former residency program directors. After residents click on their answer, the system lets them know whether they’re right and provides the correct answer with an explanation and references. Monthly notifications are sent out to all jfponline.com registered users alerting them that a new quiz is available. (Not a registered user on the site? Sign up at jfponline.com/residents_reg.)

Getting ready for the recertification exam? The RRR quizzes can help you, too. Check out the latest quiz, today!

The results of the 2015 National Residency Match Program were announced on March 20. For family medicine, the glass was either half empty or half full, depending on your point of view.

On the plus side, 84 more family medicine positions were offered compared to 2014 (3216 vs 3132) and 60 more positions were filled, for a total of 3060 new family medicine residents in 2015.¹ This was far more than matched in gloomy 2009, when only 2555 residents chose family medicine. On the negative side of the balance sheet, there will be 233 fewer family medicine residents this year than matched at the peak of medical student interest in family medicine in 1998.

I’m a glass half full kind of guy, so I am delighted that the trend of increased medical student interest in family medicine continues. According to Merritt Hawkins, a national recruitment firm, family medicine has been the top recruited specialty for several years. The firm reports that starting salaries for family physicians increased by nearly 12% from 2010/11 to 2013/14, which was a higher rate than that of most other specialties.² So there is reason to be optimistic about the future of our specialty.

Our monthly 5-question online quiz can help residents study for their certification exam.

However, to be card-carrying family physicians, our new residents must take the American Board of Family Medicine certification exam, and not all pass on their first attempt. A 2013 study of family medicine residency graduates found that only 86% of graduates passed the board exam on their first try.³

We can help. In addition to the evidence-based reviews published in The Journal of Family Practice (JFP), we have launched a new feature called Residents’ Rapid Review (RRR) to provide an additional resource for residents.

RRR is a monthly 5-question evidence-based quiz prepared by primary care faculty, including current and former residency program directors. After residents click on their answer, the system lets them know whether they’re right and provides the correct answer with an explanation and references. Monthly notifications are sent out to all jfponline.com registered users alerting them that a new quiz is available. (Not a registered user on the site? Sign up at jfponline.com/residents_reg.)

Getting ready for the recertification exam? The RRR quizzes can help you, too. Check out the latest quiz, today!

The results of the 2015 National Residency Match Program were announced on March 20. For family medicine, the glass was either half empty or half full, depending on your point of view.

On the plus side, 84 more family medicine positions were offered compared to 2014 (3216 vs 3132) and 60 more positions were filled, for a total of 3060 new family medicine residents in 2015.¹ This was far more than matched in gloomy 2009, when only 2555 residents chose family medicine. On the negative side of the balance sheet, there will be 233 fewer family medicine residents this year than matched at the peak of medical student interest in family medicine in 1998.

I’m a glass half full kind of guy, so I am delighted that the trend of increased medical student interest in family medicine continues. According to Merritt Hawkins, a national recruitment firm, family medicine has been the top recruited specialty for several years. The firm reports that starting salaries for family physicians increased by nearly 12% from 2010/11 to 2013/14, which was a higher rate than that of most other specialties.² So there is reason to be optimistic about the future of our specialty.

Our monthly 5-question online quiz can help residents study for their certification exam.

However, to be card-carrying family physicians, our new residents must take the American Board of Family Medicine certification exam, and not all pass on their first attempt. A 2013 study of family medicine residency graduates found that only 86% of graduates passed the board exam on their first try.³

We can help. In addition to the evidence-based reviews published in The Journal of Family Practice (JFP), we have launched a new feature called Residents’ Rapid Review (RRR) to provide an additional resource for residents.

RRR is a monthly 5-question evidence-based quiz prepared by primary care faculty, including current and former residency program directors. After residents click on their answer, the system lets them know whether they’re right and provides the correct answer with an explanation and references. Monthly notifications are sent out to all jfponline.com registered users alerting them that a new quiz is available. (Not a registered user on the site? Sign up at jfponline.com/residents_reg.)

Getting ready for the recertification exam? The RRR quizzes can help you, too. Check out the latest quiz, today!

THE CASE

A 38-year-old Hispanic man was brought to the emergency department (ED) after losing consciousness and falling at home, striking his elbow, head, and neck. For the past week, he’d had palpitations, shortness of breath, mild swelling of the lower extremities, fever, nausea, and fatigue. He had also been experiencing squeezing chest pain that worsened with exertion and was only partially relieved by nitroglycerin.

The patient did not have any rashes and denied having contact with anyone who was sick. He said that he’d been bitten by mosquitos during recent outdoor activities. His medical history included hypertension, hemorrhagic basal ganglia stroke, hyperlipidemia, sleep apnea, metabolic syndrome, and gout. The patient denied smoking or using illicit drugs.

In the ED, his temperature was 101°F, heart rate was 112 beats/min, blood pressure was 175/100 mm Hg, and respiratory rate was 18 breaths/min. His head and neck exam was normal, with no neck stiffness. A lung exam revealed bilateral basal crackles, and a neurologic exam showed residual right-sided weakness due to the hemorrhagic stroke one year ago.

Lab test results revealed the following: white blood cell (WBC) count, 13,000/mm³ with relative monocytosis (14%); lymphocytosis (44%) with normal neutrophils and no bands; hemoglobin, 12 g/dL; hematocrit, 36/mm³; and platelets, 300,000/mm³. Liver function tests were within normal limits. Urinalysis was unremarkable. His troponin I level was elevated at 1.385 ng/dL. In addition to the tachycardia, his electrocardiogram (EKG) showed left axis deviation, left atrial enlargement, left anterior fascicular block, and diffuse nonspecific ST and T wave abnormalities. Chest x-ray was unremarkable except for cardiomegaly. A computed tomography (CT) scan of his head showed residual changes from the previous stroke.

The patient was admitted with a provisional diagnosis of systemic inflammatory response syndrome (SIRS), syncope, non–ST elevation myocardial infarction (NSTEMI), and acute heart failure. The patient had continuous EKG monitoring and serial assessments of his troponin levels. He was also given aspirin, metoprolol 25 mg BID, lisinopril 10 mg/d, furosemide 40 mg IV, isosorbide mononitrate 60 mg/d, and atorvastatin 40 mg/d.

The patient’s cardiac enzymes subsequently decreased. A left heart catheterization was performed, which showed minimum irregularities of the left anterior descending artery (< 20% narrowing) and an ejection fraction (EF) of 35%, without any evidence of obstructive coronary artery disease (CAD). An echocardiogram revealed systolic dysfunction, with an EF of 35% to 40% and global hypokinesis without any apical ballooning or pericardial effusion. (An echocardiogram performed 6 months earlier had shown normal systolic function, an EF of 60% to 65%, and no wall motion abnormalities.) Blood, urine, and fungal cultures were negative; stool studies for ova and parasites were also negative. A lower extremity venous Doppler was negative for deep vein thrombosis.

THE DIAGNOSIS

Because our patient had SIRS, troponinemia, acute systolic dysfunction, and global hypokinesis without any evidence of obstructive CAD, we considered a diagnosis of viral myocarditis. Serologic studies for echovirus, coxsackievirus B, parvovirus B19, adenovirus, and human herpesvirus 6 (HHV-6) all came back negative. However, an enzyme-linked immunosorbent assay (ELISA) for West Nile virus (WNV) was positive. WNV infection was confirmed with a positive plaque reduction neutralization test and a positive qualitative polymerase chain reaction (PCR) assay, which established a diagnosis of WNV myocarditis.

DISCUSSION

While most individuals infected with WNV are asymptomatic, 20% to 40% of patients will exhibit symptoms.^1-4 Typical presentations of WNV infection include West Nile fever and neuroinvasive disease. West Nile fever is a self-limited illness characterized by a low-grade fever, headache, malaise, back pain, myalgia, and anorexia for 3 to 6 days.² Neuroinvasive disease caused by WNV may present as encephalitis, meningitis, or flaccid paralysis.⁵ Atypical presentations of the virus include rhabdomyolysis,⁶ fatal hemorrhagic fever with multi-organ failure and palpable purpura,⁷ hepatitis,⁸ pancreatitis,⁹ central diabetes insipidus,¹⁰ and myocarditis.¹¹

Although WNV has been linked to myocarditismin animals,¹² few human cases of WNV myocarditis^11,13 or cardiomyopathy¹⁴ have been reported. Viral myocarditis often leads to the development of dilated cardiomyopathy, and myocardial damage may result from direct virus-induced cytotoxicity, T cell-mediated immune response to the virus, or apoptosis.¹⁵ Some research suggests that immune-mediated mechanisms play a primary role in myocardial damage. Caforio et al¹⁶ found that anti-alpha myosin antibodies were present in 34% of myocarditis patients. In a follow-up study, these antibodies were shown to persist for up to 6 months, which far surpasses the viral cardiac replication timeline of 2 to 3 weeks,¹⁷ suggesting that damage occurring after that time is primarily an autoimmune process.

The differential diagnosis for WNV myocarditis includes myocardial stunning from demand ischemia related to SIRS, Takotsubo cardiomyopathy (stress cardiomyopathy), and Dressler’s syndrome. For our patient, myocardial stunning from demand ischemia was less likely because he had no obstructive coronary disease or focal hypokinesis. In addition, the persistence of left ventricular systolic dysfunction and global hypokinesis demonstrated in a repeat echocardiogram during follow-up 6 months later reinforced the likelihood of myocarditis.

Although West Nile virus has been linked to myocarditis in animals, few human cases of WNV myocarditis or cardiomyopathy have been reported.

The patient’s chest pain with syncope, elevated troponin level, and nonspecific EKG changes in the absence of obstructive CAD raised the possibility of Takotsubo cardiomyopathy. The characteristic echocardiogram finding in Takotsubo cardiomyopathy is transient apical ballooning with akinesis or hypokinesis in the apical and/or mid ventricular regions (typical variant) or isolated midventricular hypokinesis (apical sparing variant). Our patient’s echocardiogram did not show any of these focal wall motion abnormalities, but instead showed global hypokinesis. In addition, the persistence of systolic dysfunction during the repeat echocardiogram and the patient’s lack of psychological distress made the diagnosis of Takotsubo cardiomyopathy unlikely.

Dressler’s syndrome, which is also known as post-myocardial infarction (MI) syndrome, typically presents weeks to months after MI as pleuritic chest pain with a pericardial rub, elevated inflammatory markers, typical EKG changes (diffuse ST-segment elevation and PR-segment depression), and pericardial effusion. This did not fit our patient’s presentation.

Supportive care for heart failure is the mainstay of treatment

The standard treatment for WNV myocarditis is supportive care. Diuretics are used as needed for fluid overload, along with angiotensin-converting enzyme inhibitors and beta-blockers for cardiomyopathy with decreased EF.

Our patient’s dyspnea improved with treatment of furosemide 40 mg IV BID, and his blood pressure was controlled with metoprolol 25 mg BID and lisinopril 10 mg BID. His chest pain and fever resolved when his blood pressure improved. He was discharged home after 7 days on the furosemide, metoprolol, and lisinopril, in addition to isosorbide mononitrate 30 mg/d, atorvastatin 40 mg/d, and aspirin 325 mg/d. An echocardiogram performed 6 months later showed persistent systolic dysfunction, with an EF of 35% and global wall motion abnormalities.

THE TAKEAWAY

In addition to acute coronary syndrome, consider alternate etiologies in patients who present with chest pain and elevated cardiac biomarkers, particularly if diagnostic work-up is negative for obstructive coronary artery disease. WNV myocarditis should be considered as a diagnosis when a patient’s symptoms suggest acute coronary syndrome but are accompanied by fever, headache, and other constitutional symptoms, especially during mosquito season or a WNV outbreak.

THE CASE

A 38-year-old Hispanic man was brought to the emergency department (ED) after losing consciousness and falling at home, striking his elbow, head, and neck. For the past week, he’d had palpitations, shortness of breath, mild swelling of the lower extremities, fever, nausea, and fatigue. He had also been experiencing squeezing chest pain that worsened with exertion and was only partially relieved by nitroglycerin.

The patient did not have any rashes and denied having contact with anyone who was sick. He said that he’d been bitten by mosquitos during recent outdoor activities. His medical history included hypertension, hemorrhagic basal ganglia stroke, hyperlipidemia, sleep apnea, metabolic syndrome, and gout. The patient denied smoking or using illicit drugs.

In the ED, his temperature was 101°F, heart rate was 112 beats/min, blood pressure was 175/100 mm Hg, and respiratory rate was 18 breaths/min. His head and neck exam was normal, with no neck stiffness. A lung exam revealed bilateral basal crackles, and a neurologic exam showed residual right-sided weakness due to the hemorrhagic stroke one year ago.

Lab test results revealed the following: white blood cell (WBC) count, 13,000/mm³ with relative monocytosis (14%); lymphocytosis (44%) with normal neutrophils and no bands; hemoglobin, 12 g/dL; hematocrit, 36/mm³; and platelets, 300,000/mm³. Liver function tests were within normal limits. Urinalysis was unremarkable. His troponin I level was elevated at 1.385 ng/dL. In addition to the tachycardia, his electrocardiogram (EKG) showed left axis deviation, left atrial enlargement, left anterior fascicular block, and diffuse nonspecific ST and T wave abnormalities. Chest x-ray was unremarkable except for cardiomegaly. A computed tomography (CT) scan of his head showed residual changes from the previous stroke.

The patient was admitted with a provisional diagnosis of systemic inflammatory response syndrome (SIRS), syncope, non–ST elevation myocardial infarction (NSTEMI), and acute heart failure. The patient had continuous EKG monitoring and serial assessments of his troponin levels. He was also given aspirin, metoprolol 25 mg BID, lisinopril 10 mg/d, furosemide 40 mg IV, isosorbide mononitrate 60 mg/d, and atorvastatin 40 mg/d.

The patient’s cardiac enzymes subsequently decreased. A left heart catheterization was performed, which showed minimum irregularities of the left anterior descending artery (< 20% narrowing) and an ejection fraction (EF) of 35%, without any evidence of obstructive coronary artery disease (CAD). An echocardiogram revealed systolic dysfunction, with an EF of 35% to 40% and global hypokinesis without any apical ballooning or pericardial effusion. (An echocardiogram performed 6 months earlier had shown normal systolic function, an EF of 60% to 65%, and no wall motion abnormalities.) Blood, urine, and fungal cultures were negative; stool studies for ova and parasites were also negative. A lower extremity venous Doppler was negative for deep vein thrombosis.

THE DIAGNOSIS

Because our patient had SIRS, troponinemia, acute systolic dysfunction, and global hypokinesis without any evidence of obstructive CAD, we considered a diagnosis of viral myocarditis. Serologic studies for echovirus, coxsackievirus B, parvovirus B19, adenovirus, and human herpesvirus 6 (HHV-6) all came back negative. However, an enzyme-linked immunosorbent assay (ELISA) for West Nile virus (WNV) was positive. WNV infection was confirmed with a positive plaque reduction neutralization test and a positive qualitative polymerase chain reaction (PCR) assay, which established a diagnosis of WNV myocarditis.

DISCUSSION

While most individuals infected with WNV are asymptomatic, 20% to 40% of patients will exhibit symptoms.^1-4 Typical presentations of WNV infection include West Nile fever and neuroinvasive disease. West Nile fever is a self-limited illness characterized by a low-grade fever, headache, malaise, back pain, myalgia, and anorexia for 3 to 6 days.² Neuroinvasive disease caused by WNV may present as encephalitis, meningitis, or flaccid paralysis.⁵ Atypical presentations of the virus include rhabdomyolysis,⁶ fatal hemorrhagic fever with multi-organ failure and palpable purpura,⁷ hepatitis,⁸ pancreatitis,⁹ central diabetes insipidus,¹⁰ and myocarditis.¹¹

Although WNV has been linked to myocarditismin animals,¹² few human cases of WNV myocarditis^11,13 or cardiomyopathy¹⁴ have been reported. Viral myocarditis often leads to the development of dilated cardiomyopathy, and myocardial damage may result from direct virus-induced cytotoxicity, T cell-mediated immune response to the virus, or apoptosis.¹⁵ Some research suggests that immune-mediated mechanisms play a primary role in myocardial damage. Caforio et al¹⁶ found that anti-alpha myosin antibodies were present in 34% of myocarditis patients. In a follow-up study, these antibodies were shown to persist for up to 6 months, which far surpasses the viral cardiac replication timeline of 2 to 3 weeks,¹⁷ suggesting that damage occurring after that time is primarily an autoimmune process.

The differential diagnosis for WNV myocarditis includes myocardial stunning from demand ischemia related to SIRS, Takotsubo cardiomyopathy (stress cardiomyopathy), and Dressler’s syndrome. For our patient, myocardial stunning from demand ischemia was less likely because he had no obstructive coronary disease or focal hypokinesis. In addition, the persistence of left ventricular systolic dysfunction and global hypokinesis demonstrated in a repeat echocardiogram during follow-up 6 months later reinforced the likelihood of myocarditis.

Although West Nile virus has been linked to myocarditis in animals, few human cases of WNV myocarditis or cardiomyopathy have been reported.

The patient’s chest pain with syncope, elevated troponin level, and nonspecific EKG changes in the absence of obstructive CAD raised the possibility of Takotsubo cardiomyopathy. The characteristic echocardiogram finding in Takotsubo cardiomyopathy is transient apical ballooning with akinesis or hypokinesis in the apical and/or mid ventricular regions (typical variant) or isolated midventricular hypokinesis (apical sparing variant). Our patient’s echocardiogram did not show any of these focal wall motion abnormalities, but instead showed global hypokinesis. In addition, the persistence of systolic dysfunction during the repeat echocardiogram and the patient’s lack of psychological distress made the diagnosis of Takotsubo cardiomyopathy unlikely.

Dressler’s syndrome, which is also known as post-myocardial infarction (MI) syndrome, typically presents weeks to months after MI as pleuritic chest pain with a pericardial rub, elevated inflammatory markers, typical EKG changes (diffuse ST-segment elevation and PR-segment depression), and pericardial effusion. This did not fit our patient’s presentation.

Supportive care for heart failure is the mainstay of treatment

The standard treatment for WNV myocarditis is supportive care. Diuretics are used as needed for fluid overload, along with angiotensin-converting enzyme inhibitors and beta-blockers for cardiomyopathy with decreased EF.

Our patient’s dyspnea improved with treatment of furosemide 40 mg IV BID, and his blood pressure was controlled with metoprolol 25 mg BID and lisinopril 10 mg BID. His chest pain and fever resolved when his blood pressure improved. He was discharged home after 7 days on the furosemide, metoprolol, and lisinopril, in addition to isosorbide mononitrate 30 mg/d, atorvastatin 40 mg/d, and aspirin 325 mg/d. An echocardiogram performed 6 months later showed persistent systolic dysfunction, with an EF of 35% and global wall motion abnormalities.

THE TAKEAWAY

In addition to acute coronary syndrome, consider alternate etiologies in patients who present with chest pain and elevated cardiac biomarkers, particularly if diagnostic work-up is negative for obstructive coronary artery disease. WNV myocarditis should be considered as a diagnosis when a patient’s symptoms suggest acute coronary syndrome but are accompanied by fever, headache, and other constitutional symptoms, especially during mosquito season or a WNV outbreak.

THE CASE

A 38-year-old Hispanic man was brought to the emergency department (ED) after losing consciousness and falling at home, striking his elbow, head, and neck. For the past week, he’d had palpitations, shortness of breath, mild swelling of the lower extremities, fever, nausea, and fatigue. He had also been experiencing squeezing chest pain that worsened with exertion and was only partially relieved by nitroglycerin.

The patient did not have any rashes and denied having contact with anyone who was sick. He said that he’d been bitten by mosquitos during recent outdoor activities. His medical history included hypertension, hemorrhagic basal ganglia stroke, hyperlipidemia, sleep apnea, metabolic syndrome, and gout. The patient denied smoking or using illicit drugs.

In the ED, his temperature was 101°F, heart rate was 112 beats/min, blood pressure was 175/100 mm Hg, and respiratory rate was 18 breaths/min. His head and neck exam was normal, with no neck stiffness. A lung exam revealed bilateral basal crackles, and a neurologic exam showed residual right-sided weakness due to the hemorrhagic stroke one year ago.

Lab test results revealed the following: white blood cell (WBC) count, 13,000/mm³ with relative monocytosis (14%); lymphocytosis (44%) with normal neutrophils and no bands; hemoglobin, 12 g/dL; hematocrit, 36/mm³; and platelets, 300,000/mm³. Liver function tests were within normal limits. Urinalysis was unremarkable. His troponin I level was elevated at 1.385 ng/dL. In addition to the tachycardia, his electrocardiogram (EKG) showed left axis deviation, left atrial enlargement, left anterior fascicular block, and diffuse nonspecific ST and T wave abnormalities. Chest x-ray was unremarkable except for cardiomegaly. A computed tomography (CT) scan of his head showed residual changes from the previous stroke.

The patient was admitted with a provisional diagnosis of systemic inflammatory response syndrome (SIRS), syncope, non–ST elevation myocardial infarction (NSTEMI), and acute heart failure. The patient had continuous EKG monitoring and serial assessments of his troponin levels. He was also given aspirin, metoprolol 25 mg BID, lisinopril 10 mg/d, furosemide 40 mg IV, isosorbide mononitrate 60 mg/d, and atorvastatin 40 mg/d.

The patient’s cardiac enzymes subsequently decreased. A left heart catheterization was performed, which showed minimum irregularities of the left anterior descending artery (< 20% narrowing) and an ejection fraction (EF) of 35%, without any evidence of obstructive coronary artery disease (CAD). An echocardiogram revealed systolic dysfunction, with an EF of 35% to 40% and global hypokinesis without any apical ballooning or pericardial effusion. (An echocardiogram performed 6 months earlier had shown normal systolic function, an EF of 60% to 65%, and no wall motion abnormalities.) Blood, urine, and fungal cultures were negative; stool studies for ova and parasites were also negative. A lower extremity venous Doppler was negative for deep vein thrombosis.

THE DIAGNOSIS

Because our patient had SIRS, troponinemia, acute systolic dysfunction, and global hypokinesis without any evidence of obstructive CAD, we considered a diagnosis of viral myocarditis. Serologic studies for echovirus, coxsackievirus B, parvovirus B19, adenovirus, and human herpesvirus 6 (HHV-6) all came back negative. However, an enzyme-linked immunosorbent assay (ELISA) for West Nile virus (WNV) was positive. WNV infection was confirmed with a positive plaque reduction neutralization test and a positive qualitative polymerase chain reaction (PCR) assay, which established a diagnosis of WNV myocarditis.

DISCUSSION

While most individuals infected with WNV are asymptomatic, 20% to 40% of patients will exhibit symptoms.^1-4 Typical presentations of WNV infection include West Nile fever and neuroinvasive disease. West Nile fever is a self-limited illness characterized by a low-grade fever, headache, malaise, back pain, myalgia, and anorexia for 3 to 6 days.² Neuroinvasive disease caused by WNV may present as encephalitis, meningitis, or flaccid paralysis.⁵ Atypical presentations of the virus include rhabdomyolysis,⁶ fatal hemorrhagic fever with multi-organ failure and palpable purpura,⁷ hepatitis,⁸ pancreatitis,⁹ central diabetes insipidus,¹⁰ and myocarditis.¹¹

Although WNV has been linked to myocarditismin animals,¹² few human cases of WNV myocarditis^11,13 or cardiomyopathy¹⁴ have been reported. Viral myocarditis often leads to the development of dilated cardiomyopathy, and myocardial damage may result from direct virus-induced cytotoxicity, T cell-mediated immune response to the virus, or apoptosis.¹⁵ Some research suggests that immune-mediated mechanisms play a primary role in myocardial damage. Caforio et al¹⁶ found that anti-alpha myosin antibodies were present in 34% of myocarditis patients. In a follow-up study, these antibodies were shown to persist for up to 6 months, which far surpasses the viral cardiac replication timeline of 2 to 3 weeks,¹⁷ suggesting that damage occurring after that time is primarily an autoimmune process.

The differential diagnosis for WNV myocarditis includes myocardial stunning from demand ischemia related to SIRS, Takotsubo cardiomyopathy (stress cardiomyopathy), and Dressler’s syndrome. For our patient, myocardial stunning from demand ischemia was less likely because he had no obstructive coronary disease or focal hypokinesis. In addition, the persistence of left ventricular systolic dysfunction and global hypokinesis demonstrated in a repeat echocardiogram during follow-up 6 months later reinforced the likelihood of myocarditis.

Although West Nile virus has been linked to myocarditis in animals, few human cases of WNV myocarditis or cardiomyopathy have been reported.

The patient’s chest pain with syncope, elevated troponin level, and nonspecific EKG changes in the absence of obstructive CAD raised the possibility of Takotsubo cardiomyopathy. The characteristic echocardiogram finding in Takotsubo cardiomyopathy is transient apical ballooning with akinesis or hypokinesis in the apical and/or mid ventricular regions (typical variant) or isolated midventricular hypokinesis (apical sparing variant). Our patient’s echocardiogram did not show any of these focal wall motion abnormalities, but instead showed global hypokinesis. In addition, the persistence of systolic dysfunction during the repeat echocardiogram and the patient’s lack of psychological distress made the diagnosis of Takotsubo cardiomyopathy unlikely.

Dressler’s syndrome, which is also known as post-myocardial infarction (MI) syndrome, typically presents weeks to months after MI as pleuritic chest pain with a pericardial rub, elevated inflammatory markers, typical EKG changes (diffuse ST-segment elevation and PR-segment depression), and pericardial effusion. This did not fit our patient’s presentation.

Supportive care for heart failure is the mainstay of treatment

The standard treatment for WNV myocarditis is supportive care. Diuretics are used as needed for fluid overload, along with angiotensin-converting enzyme inhibitors and beta-blockers for cardiomyopathy with decreased EF.

Our patient’s dyspnea improved with treatment of furosemide 40 mg IV BID, and his blood pressure was controlled with metoprolol 25 mg BID and lisinopril 10 mg BID. His chest pain and fever resolved when his blood pressure improved. He was discharged home after 7 days on the furosemide, metoprolol, and lisinopril, in addition to isosorbide mononitrate 30 mg/d, atorvastatin 40 mg/d, and aspirin 325 mg/d. An echocardiogram performed 6 months later showed persistent systolic dysfunction, with an EF of 35% and global wall motion abnormalities.

THE TAKEAWAY

In addition to acute coronary syndrome, consider alternate etiologies in patients who present with chest pain and elevated cardiac biomarkers, particularly if diagnostic work-up is negative for obstructive coronary artery disease. WNV myocarditis should be considered as a diagnosis when a patient’s symptoms suggest acute coronary syndrome but are accompanied by fever, headache, and other constitutional symptoms, especially during mosquito season or a WNV outbreak.