AJCM Winter 2011 by American Board of Physician Specialties (ABPS)

American Journal of Clinical MedicineÂŽ Owned and Published by the American Association of Physician Specialists, Inc.

Featured in This Issue 6 Review of Medical and Surgical Management of Postpartum Hemorrhage 11 Transfuse or Not to Transfuse: For Post-op Anemia 15 A Critical Appraisal of the Evolution of ST Elevation Myocardial Infarction (STEMI) Therapy and the Evidence Behind the Current Treatment Guidelines 40 Malignant and Benign Eyelid Lesions in San Francisco: Study of a Diverse Urban Population 47 Invasive Squamous Cell Carcinoma of the Cervix Following HPV Immunization in a Nineteen-Year-Old Woman 49 Impact of a Multi-Modality Intervention on Physician Knowledge and Practice in Managing Hepatitis C 57

Primary Mature Cystic Teratoma of the Liver: Report of a Rare Case

65 The Role of Physician Experience in Pelvic Examination Accuracy

Winter 2011 â&#x20AC;˘ Volume Eight, Number One

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The American Journal of Clinical Medicine® (AJCM®) is the official, peer-reviewed journal of the American Association of Physician Specialists, Inc. (AAPS), an organization dedicated to promoting the highest intellectual, moral, and ethical standards of its members. Its diversity incorporates physicians that represent a broad spectrum of specialties including anesthesiology, dermatology, diagnostic radiology, disaster medicine, emergency medicine, family medicine/OB, family practice, geriatric medicine, hospital medicine, internal medicine, obstetrics and gynecology, ophthalmology, orthopedic surgery, plastic and reconstructive surgery, psychiatry, radiation oncology, general surgery, and urgent care medicine.

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To further the goals of AAPS, which include providing education for its members and promoting the study, research, and improvement of its various specialties, the AJCM® invites submissions of high-quality review articles, clinical reports, case reports, or original research on any topic which has potential to impact the daily practice of medicine. Publication in the AJCM® is one of the criteria to qualify for the prestigious Degree of Fellow within the Academies of Medicine of the AAPS.

AJCM

Daniel M. Avery, Jr., MD, FAASS Dwight Hooper, MD, MBA

In This Issue 2010 Annual Meeting Proceedings Review of Medical and Surgical Management of Postpartum Hemorrhage

49 6

Jasmine Chao, DO, MS, FAAFP

A Critical Appraisal of the Evolution of ST Elevation Myocardial Infarction (STEMI) Therapy and the Evidence Behind the Current Treatment Guidelines

57 15

Leslie Mukau MD, FAAEP, FACEP



Malignant and Benign Eyelid Lesions in San Francisco: Study of a Diverse Urban Population Sean Paul, MD Dat T. Vo, BS Rona Z. Silkiss, MD, FACS

65 40

Sounding Board: NOT Flat Stanley’s Big Vacation Dr. Ed Thornton on Foreign Medical Work Martin E. Thornton, DO

Mark Pastin, PhD

Primary Mature Cystic Teratoma of the Liver: Report of a Rare Case Brian Harris, PhD, MD, FAAR Nicole De Simone, DO, MPH



Medical Ethics: Never Too Old For Love

Impact of a Multi-Modality Intervention on Physician Knowledge and Practice in Managing Hepatitis C M. Rebecca Daniel, MD, FACP Bonita Singal, MD, PhD Varsha Moudgal, MD Thomas M. Shehab, MD, FACP, FACG

Daniel M. Avery, Jr., MD, FAASS

Transfuse or Not to Transfuse: For Post-op Anemia

Invasive Squamous Cell Carcinoma of the Cervix Following HPV Immunization in a Nineteen-Year-Old Woman

The Role of Physician Experience in Pelvic Examination Accuracy Daniel M. Avery, Jr., MD, FAASS Jason M. Parton, MA, MS John C. Higginbotham, PhD, MPH

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AAPS Board of Directors Babu J. Amin, MD William G. Anderson, DO Harold M. Bacchus, Jr., MD, FAASFP Scott G. Barnes, DO, FAAIM William M. Castillo, MD, FAASS A. Robert Cerrato, DO, JD William Lee Irwin, II, MD Karl David Kelley, MD Peter A. Lawrence, MD, JD Gia Danh Le, MD Jerry R. Majers, DO, FAAIM, FAAGM Douglas L. Marciniak, DO, FAAIM David G.C. McCann, MD, FAASFP Stephen A. Montes, DO, FAASOS Robert W. Moore, DO, FAASOS Herbert Pardell, DO, FAAIM Anthony P. Russo, Jr., DO, FAAA Betsy B. Schenck, DO, FAAEP Louis W. Sullivan, MD

AAPS Staff William J. Carbone Chief Executive Officer Nadine B. Simone Executive Assistant Arrie A. Potter Assistant Director of Certification, Test Development & Scoring Andrea N. Balboa Assistant Director of Certification, Test Administration & Customer Care Susan LoBianco Certification Coordinator Marilyn D. Whitfield Certification Coordinator Maria F. Valente Certification Coordinator Esther L. Berg Director of CME, Meetings & Membership Keely M. Clarke CME, Meetings & Membership Coordinator Anthony J. Durante Director of Finance & Operations Georgine C. Wasser Finance & Operations Coordinator Debi S. Colmorgen Communications Coordinator Bruce Cotton Director of Governmental Affairs Jeffery L. Morris, Jr., JD Manager of Governmental Affairs Lauren E. Withrow Governmental Affairs Coordinator James G. Marzano Director of Public Relations & Marketing

elcome to the American Journal of Clinical Medicine® (AJCM®). This issue includes several presentations from the 2010 Annual Scientific Meeting. The Journal is dedicated to improving the practice of clinical medicine by providing up-to-date information for today’s practitioners. The AJCM is the official journal of the American Association of Physician Specialists, Inc. (AAPS), an organization dedicated to promoting the highest intellectual, moral, and ethical standards of its members, and whose diversity incorporates physicians that represent a broad spectrum of specialties including anesthesiology, dermatology, diagnostic radiology, disaster medicine, emergency medicine, family medicine obstetrics, family practice, geriatric medicine, hospital medicine, internal medicine, obstetrics and gynecology, ophthalmology, orthopedic surgery, plastic and reconstructive surgery, psychiatry, radiation oncology, general surgery, and urgent care medicine. Part of the mission of the AAPS is to provide education for its members and to promote study, research, and improvement of its various specialties. In order to further these goals, the AJCM invites submissions of high-quality review articles, clinical reports, case reports, or original research on any topic that has potential to impact the daily practice of medicine. Publication of a peer-reviewed article in the AJCM is one of the criteria needed to qualify for the prestigious Degree of Fellow in the Academies of Medicine of the AAPS. Articles that appear in the AJCM are peer reviewed by members with expertise in their respective specialties. Manuscripts submitted for publication should follow the guidelines in The International Committee of Medical Journal Editors: “Uniform requirements for manuscripts submitted to biomedical journals” (JAMA, 1997; 277:927-934). Studies involving human subjects must adhere to the ethical principals of the Declaration of Helsinki, developed by the World Medical Association. By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of their article that might create any potential conflict of interest. More detailed information is included in the AJCM Manuscript Criteria and Information on pages 60 and 61. All articles published, including editorials, letters, and book reviews, represent the opinions of the authors and do not reflect the official policy of the American Association of Physician Specialists, Inc., or the institution with which the author is affiliated, unless this is clearly specified. ©2011 American Journal of Clinical Medicine® is published by the American Association of Physician Specialists, Inc. All rights reserved. Reproduction without permission is prohibited. Although all advertising material is expected to conform to ethical standards, acceptance does not imply endorsement by the American Journal of Clinical Medicine® and the American Association of Physician Specialists, Inc.

Editor-In-Chief

Wm. MacMillan Rodney, MD, FAAFP, FACEP

Senior Editor

Kenneth M. Flowe, MD, FAAEP

Managing Editor

Esther L. Berg, MEd

Editorial Board

Harold M. Bacchus, Jr., MD, FAAFP Gilbert Daniel, MD, FAAR Michael K. Garey, MD Robert J. Geller, DO, FAAEP Thomas A. Gionis, MD, JD Beverly R. Goode-Kanawati, DO Thomas G. Pelz, DO, FAAIM Cyril H. Wecht, MD, JD

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AJCM

Welcome to the New Year – 2011

Since 1975, my goals have been to provide exemplary continuing health care for my patients and outstanding educational experiences for my students, residents, and colleagues. It is an honor and privilege to serve as editor of the American Journal of Clinical Medicine® (AJCM®). Authors who produce quality manuscripts must be solicited, encouraged, nurtured, and published. Writing is a labor of love. The only thing more difficult than writing is rewriting. Welcome to the world of publication. All of us will benefit through the prosperity of the AJCM enterprise. I propose a vision described by a circular hierarchy of seven activities. These are: patient care, education, scholarship, administration, ambassadorship, leadership, and legacy. In 1999 I designed and built a private practice hoping to improve upon the seemingly insolvable problems witnessed during my career as a Professor and Chair in several medical schools. By 1999 I had a seven-year history with the AAPS, since I was co-director of a fellowship in Emergency Medicine (BCEM). My current practice is built on a foundation of family medicine but combines Public Health, Obstetrics including Cesareans, Emergency Care, and International Mission Hospitals. Without grants or charity, my practice funds an active teaching program and clinical research encompassing almost all of the established specialties. I have served as an author and/or editor for over 200 publications and compliment my predecessors and staff for establishing and maintaining the ACJM. Thank you.

The AJCM is now being cited as part of the international community of scholars. Our 2009 and 2010 editions are in the process of being included in Google Scholar and BioMedLib. The engines are more extensive than PubMed, which is next. This gives published authors international recognition at achievin a universal academic standard of excellence. With this membership, AJCM joins the major leagues of science – published work will last as long as our civilization does. WE must fund our efforts and make the transition to multimedia via the internet. This will require committed editorial board members that unselfishly devote themselves to timely peer review of manuscripts. WE must maintain an impeccable reputation for quality and integrity. WE should be part of a national campaign supporting recognition of the AJCM as a medical journal offering useful information for the practicing physician.

There are so many worthy causes, but the AJCM should be a journal that emphasizes the issues which make the AAPS so important for physicians who have been challenged by training cartels and economic credentialing monopolies. Our research should demonstrate the role of privilege based on MERIT. The AAPS and the AJCM will develop a nationally recognized leadership position through recognition of its authors and their published research. “Medicos – where 10 percent of the information makes over 90 percent of the difference and where, through Grace, twice the service is provided at less than half of the cost.”

Wm. MacMillan Rodney MD, FAAFP, FACEP

Editor, American Journal of Clinical Medicine® Member, American Board of Family Medicine Obstetrics

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

ABPS Becomes Corporate Partner with NRHA

“We’re pleased to announce the American Board of Physician Specialties® has become a corporate partner with the National Rural Health Association (NRHA),” said CEO William J. Carbone. ABPS’ involvement with NRHA provides a valuable resource to help us proactively identify needs and trends within the rural health care market. “Focusing on the needs of local communities, including those in rural America, helps ABPS and its member Diplomates remain committed to placing patients first.” The NRHA is a national nonprofit organization with 20,000 members, providing leadership on rural health issues. “NRHA welcomes ABPS and their desire to provide world-class board certification expertise to physicians and hospitals,” says Brock Slabach, NRHA senior vice-president of member services. A complete list of NRHA partners is available at http://www.nrhasc.com/connect.

American Academy of Disaster Medicine Accepting Award Nominations Do you know an individual, organization, or community making a positive difference in emergency preparedness and disaster health care response? The American Academy of Disaster Medicine (AADM) is seeking nominations for its Distinguished Service Award, honoring deserving individuals, organizations, and communities positively affecting public health care in the disaster life cycle – preparation, planning, response, and recovery. “It is a privilege for the Academy of Disaster Medicine to present the Distinguished Service Award, since this new physician specialty plays a vital role in public health preparedness,” says Academy President Karl Kelley, MD, of Springfield, Tenn. “Promoting the building of disaster resilient communities is a national priority.” AADM is seeking nominees meeting one of the following criteria: 1. Individuals that successfully served as leader of a disaster preparedness and/or response organization with positive outcomes. 2. Organizations, governmental or non-governmental, that have demonstrated the ability to affect change in the practice of disaster preparedness and/or management response. 3. Communities that have educated, organized, and built a cohesive team of leaders in community preparedness of disaster medicine and/or management response. For submission details, visit http://www.aapsus.org/aadm-award-nomination. The deadline for submissions is April 30, 2011. Winners will be announced June 25 at the Annual Meeting of the American Association of Physician Specialists, Inc., in McLean, Va. The conference is titled “What Every Physician Should Know About Disasters.”

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Proceedings of the AAPS 2010 House of Delegates & Annual Scientific Meeting june 7 -12, 2010 Orlando, Florida

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Review of Medical and Surgical Management of Postpartum Hemorrhage Daniel M. Avery, Jr., MD, FAASS

There are two great fears for those who attend childbirth; these have not changed over centuries. The first is massive postpartum hemorrhage and the other is a shoulder dystocia. Postpartum hemorrhage is a significant cause of maternal morbidity and mortality worldwide among both developed and developing countries. This problem daily faces the 35,000 obstetrician/ gynecologists and 17,000 family physicians who deliver about a million babies yearly in this country.

Case Report #1 Early in my career, just after completing residency training, I was summoned to help another physician in the labor suite. This physician was older, very experienced, a skillful surgeon, and adept at managing almost any type of OB/GYN emergency. I was only told that he needed help as soon as I could get there. I was very suspect when I arrived, because blood was flowing out from under the closed door to the labor room. I quickly opened the door, and there was blood everywhere . . . the floor, the ceiling, the walls, the patient, the staff, and the obstetrician. There had been enough bleeding to completely cover the floor and partially cover my shoes. I had been a medical student and an OB/ GYN resident, but I had never seen anything like this. The OB/ GYN had one hand in the vagina and the other was compressing the uterus on the abdominal wall. The patient was bleeding profusely. One nurse was transfusing blood as fast as it could be squeezed in while the other nurse was summoning the blood bank for more blood. A complete blood count and coagulation profile had been drawn by the lab. As I walked into the room, the lab reported the CBC with hemoglobin of 1.5 and hematocrit of 5. I had never seen numbers that low in a living person.

The patient was very pale as would be expected. There was no urine output and no palpable vital signs. The older practitioner looked at me and said, “Got a lot of bleeding . . . will you assist me with a hysterectomy?” Although I responded with the affirmative, I did not see how this patient could possibly survive. I had never seen this much blood come from one individual. The patient was receiving blood, but it was coming out quicker than it was going in. She had three large bore IV lines. The patient was quickly moved to the cesarean section operating room for hysterectomy. The older physician and I did not scrub . . . we just put on gowns and gloves. The instruments were not counted. The patient received crash general anesthesia, and we cut. The tissues did not bleed because there was no blood in them. It reminded me of an autopsy, because those tissues do not bleed either; but, of course I was not going to say that. The operation went quickly. We did a supracervical hysterectomy and left some of the cervix. Even at the end of the hysterectomy, it did not look like she would survive – but she did. She had a long hospital course and received a lot more blood, but lived to go home. I’ve always wondered if she or her family had any idea how close she came to dying and what was involved with saving her life. The older physician thanked me for my help. I left with a great respect for massive postpartum hemorrhage.

Postpartum Hemorrhage Postpartum hemorrhage crosses the path of most specialties: OB/GYN, family medicine/ obstetrics, maternal-fetal medicine, anesthesiology, surgery, trauma, adult medicine special-

Review of Medical and Surgical Management of Postpartum Hemorrhage

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

ties (internal medicine and family medicine), medical subspecialties (pulmonary, renal, hematology/ oncology), hospitalists, intensivists, radiology including interventional, pediatricians, neonatologists, pathologists with blood bank and transfusion medicine, and urology. Should the patient expire, the pathologist may again be involved with an autopsy. Hence the old adage about a very sick patient, “Every service is seeing the patient except psychiatry.” The traditional, time-honored definition of postpartum hemorrhage is more than 500 ccs of bleeding after a vaginal delivery or more than 1,000 ccs of bleeding after a cesarean section. Unfortunately, obstetricians, like other surgeons, grossly underestimate the amount of blood loss at surgery. It is a good idea for another experienced health care provider, such as a CRNA, experienced circulating nurse, or anesthesiologist to objectively estimate the blood loss. Underestimating the blood loss makes the surgeon look good and feel good but may put the patient at risk for underestimating a significant problem. Newer definitions of postpartum hemorrhage include blood loss that causes a 10% change in hematocrit or blood loss that requires transfusion. There are several important considerations about blood loss in healthy pregnant women. There is a dilutional effect of pregnancy in which the plasma almost doubles during pregnancy out of proportion to the solid components, giving the effect of anemia. Most healthy reproductive-age women can tolerate a significant amount of blood loss without requiring transfusion. Most women can tolerate a hematocrit down to 18 or 20 without the need for receiving blood. Oral iron two or three times a day for a few weeks will normalize the hematocrit. Another consideration is the size of the uterine arteries. At term, the uterine arteries are about the size of a 3/4” garden hose. Laceration or transection can cause massive hemorrhage in a very short period of time. As a chair of a medical school OB/GYN department, I meet with students during their orientation to our service. I tell each of them that I expect that at the end of the clerkship each one will be able to deliver a baby vaginally without help or equipment in the foyer of the First Baptist Church, in the parking lot at Wal-Mart, and in the mission field in Honduras. At the end of the rotation, I confirm with each of them that they can do this. I complicate the story by telling them that they have massive postpartum hemorrhage and what can they do to manage this with no drugs or equipment. First and foremost, they can rub the fundus of the uterus against the mother’s backbone. They could compress the uterus between a hand on the fundus and a hand in the vagina. They could manually evacuate the uterus if needed. As a general rule, students’ first response to bleeding is to give the patient some pitocin. Unfortunately, there is no pitocin at churches, Wal-Mart, or the mission field. But there is natural oxytocin. Put the baby on the mother’s breast and let it suck. This releases natural oxytocin and will make the uterus contract. If she will not do this, ask her to rub her nipples as in a nipple stimulation test; this also releases natural oxytocin and will make the uterus contract.

Causes of Postpartum Hemorrhage Most cases of postpartum hemorrhage are due to uterine atony. The causes are listed in Table 1. Table 1: Causes of Uterine Atony.

Causes of Uterine Atony General anesthesia Poorly perfused myometrium in shock Overdistended uterus with multiple fetuses Excessive amniotic fluid Following rapid or prolonged labor Oxytocin induced or augmented labor Grand or high multiparity History of prior uterine atony Chorioamnionitis Uterine fibroids Placenta previa Following tocolytic therapy Following magnesium sulfate therapy Postpartum hemorrhage can also occur as the result of retained placental tissue in an avulsed cotyledon, a succinturiate or accessory lobe, an abnormally adherent placenta acreta, increta or percreta, or a placental abruption. Other causes of postpartum hemorrhage include uterine rupture, genital tract lacerations, uterine inversion, or coagulopathies.

Management of Postpartum Hemorrhage First and foremost, early in the management of postpartum hemorrhage and any massive bleeding, GET HELP! Physicians always think of this late. Inexperienced practitioners do not realize that they are in trouble and need help, while more experienced practitioners know they are in trouble but are hoping it will get better any minute, and they will not need help. Help depends on where you are. Help in a 40-bed rural hospital, where you are the only physician who delivers babies, is very different from a 600-bed teaching institution with house staff and every specialty of medicine available. In a large metropolitan, teaching hospital, often there are other OB/GYNs, trauma surgeons, general surgeons, vascular surgeons, chief residents, fellows, and family physicians that practice obstetrics. In a rural hospital, it could be a non-OB physician, a paramedic, a nurse from another floor, a family member who is a scrub tech, a unit clerk, or a maintenance worker who knows CPR or who works part-time as an ambulance attendant.

Review of Medical and Surgical Management of Postpartum Hemorrhage

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Getting help also means alerting anesthesia, the nursing staff, the blood bank, and the operating room for an impending disaster. Estimate the current blood loss and start replacing it. Inform the blood bank how much blood you need and how much you could possibly need to stay two units ahead. Any actively bleeding patient needs at least two large-bore IV lines through which blood and blood products can be transfused. Draw a CBC and coagulation factors to see where things are at the present. Try to determine the most likely source of the bleeding and the best access to it, abdominally or vaginally. Inform the patient and family of what is going on and the emergent nature of the problem.

Medical Management of Postpartum Hemorrhage The basic maneuvers in the management of postpartum hemorrhage are discussed above. Massaging the uterus and compression and evacuating the uterus will stop most bleeding. The first line of treatment for bleeding due to uterine atony is uterotonic medications. Natural pitocin or oxytocin can be elicited by breastfeeding or rubbing nipples as in a nipple stimulation test described above. Oxytocin (Pitocin) is the first line of medical therapy. It is usually available in a labor and delivery unit. It may not be available in a hospital that does not do obstetrics. It can be administered IV, IM, intrauterine, or as a continuous infusion. It works very well with massaging and compressing the uterus.1 High doses can cause water intoxication due to its antidiuretic effect, which lasts for several days. Pitocin also elevates blood pressure so its use in a hypertensive patient requires close monitoring.1 Methylergonovine (Methergine) is used to make the uterus contract. It is an old drug, and, unfortunately, it elevates blood pressure and should not be used in patients that are hypertensive or eclamptic.1 There is only one dose, and it is 0.2 mg IM q 2-4 hours. The same dose can be given orally every six hours. Prostaglandin F 2 Alpha (Hemabate) is often used when Methergine is contraindicated. The dose is 250 mcg IM or IU every 15-90 minutes up to a maximum of eight doses.1 It usually provokes the usual prostaglandin side effects of fever, red rash, nausea, vomiting, flushing, chills, and headache.1 It is contraindicated in cardiac, hepatic, pulmonary, and renal disease.1 Prostaglandin E 2 (Dinoprostone) is given as a 20 mg rectal suppository every two hours. It has the same side effects as Hemabate.1 It is contraindicated with hypotension.1 Misoprostol (Cytotec) is given as a single dose 600-1,000 mcg PO or PR.1 It has the same side effect profile as the other prostaglandins.1 It is regularly used in OB/GYN because it is very inexpensive. There are no known contraindications except an allergy to it. Calcium Gluconate is the antidote for magnesium sulfate (MgSO4) or nifedipine when these agents have been used to

relax the uterus in preterm labor or to prevent eclampsia.1 Usually one ampule is sufficient, and it is given by slowing injecting ½ ampule IV at a time. Recombinant Activated Factor VII is a synthetic vitamin Kdependent protein used successfully for intractable traumatic and surgical bleeding when everything else has failed, including hysterectomy.4 It may not be readily available in all hospitals. Transfusion of Blood and Blood Products is used as necessary to manage postpartum hemorrhage.

Case Report #2 A 35-year old Middle Eastern female p1001 presented for prenatal care following a term pregnancy two years previously that had culminated in a delivery by low transverse cesarean section. That pregnancy had been uncomplicated, and the patient was very compliant. With the current pregnancy, her only complaint was daily, painless bleeding. On vaginal speculum examination, there was blood oozing from the upper portion of the cervix. It could not be determined if this was a placenta previa or cervical pregnancy. A pelvic ultrasound was performed with the diagnosis of “cervical pregnancy.” She was referred to our main campus department of OB/GYN for maternal-fetal medicine consultation. Their diagnosis was probably very low lying placenta previa, but since there was a possibility of cervical pregnancy, termination was offered. The patient declined termination and returned to our campus for continuation of prenatal care. She presented every week for obstetrical care. She took prenatal vitamins and extra iron and maintained her hematocrit; however, she was bleeding every day. At 39 weeks gestation, a repeat low transverse cesarean section was performed by an experienced OB/GYN attending and an obstetrics fellow. The placenta was removed with some difficulty with excessive blood loss controlled with over-sewing the lower uterine segment. In the recovery room, the patient began bleeding briskly from the vagina with an estimated 2,000 ccs of blood. She lost her pulse and blood pressure before arrival of the obstetrics team. She was resuscitated by the anesthesiologist with four units of packed red blood cells and pressors. She was stabilized and returned to the operating room and re-explored. Bleeding from the lower uterine segment and cervix was massive, and a peripartal total abdominal hysterectomy was performed. The patient was transferred to the Surgical Intensive Care Unit in stable condition. She continued to receive blood and blood products along with pressors. Pulmonary, renal, and intensive care services were consulted. She became hypotensive that afternoon and was re-explored by trauma surgery, general and vascular surgery, and three OB/GYN senior attending physicians, and the bleeding stabilized. She was given more blood and blood products including cryoprecipitate. Urology repaired a laceration of the bladder from the previous operation. The following day she became hypotensive and was re-explored again. At this point, the blood bank, which serves a 600-bed hospital and trauma center, had been depleted of blood and blood prod-

Review of Medical and Surgical Management of Postpartum Hemorrhage

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

ucts twice. Activated Factor VII was obtained from the American Red Cross 45 miles away and relayed to the hospital by the Alabama State Police. The Activated Factor VII was given as a last resort to control bleeding and her bleeding ceased. She was closed and eventually resumed bowel and bladder function. She was discharged home about postoperative day ten. She has done well since that time.

Surgical Management of Postpartum Hemorrhage There are many surgical methods used to control bleeding from the uterus in a postpartum hemorrhage as listed in Table 2. Table 2: Surgical Management of Bleeding.

Exploration of the uterus if not done already Compression of the uterus Continuous bimanual massage Fundal compression Lap packs tied around the uterus Closed massage of the abdomen Hot intrauterine douches are no longer used Packing to control bleeding Vaginal packing Uterine packing (requires anesthesia) Packing other sites Umbrella pack in the pelvis after hysterectomy Temporary vascular occlusion Rubber-shod Kelley clamps across the uterine and utero-ovarian vessels Compression of the aorta— ALWAYS ALERT ANESTHESIA!! Arterial ligation O’Leary-O’Leary ligation of the uterine vessels Hypogastric artery ligation Ligation of utero-ovarian vessels Compression sutures B-Lynch sutures Uterine over-sewing Multiple square knots in the myometrium Segmental resection of myometrial wall Selective arterial embolization1 Cesarean hysterectomy Supracervical hysterectomy Total abdominal hysterectomy Exploration of the uterus can be performed, if not already done, abdominally if the abdomen is open or vaginally if closed or following a vaginal delivery. Remaining fragments of placenta or clots preventing contraction of the uterus should be removed.

Compression of the uterus can be performed manually with abdomen open between two hands to control bleeding. If the abdomen has been closed or in a vaginal delivery, the uterus can be compressed by one hand in the vagina and one on the abdomen, bearing in mind that, if the patient is without anesthesia, this may be painful. Lap packs can be tied around the uterus if the abdomen is open to control bleeding. Hot intrauterine douches are no longer used to control bleeding but are mentioned for completeness sake.2 Packing has been used by OB/GYNs for centuries to control bleeding from the uterus, cervix, and vagina and can be used in other sites as well. Packing tamponades bleeding vessels to allow the natural clotting cascade to occur, which should be successful within one hour if there are no coagulation defects.3 Patients cannot tolerate uterine packing without anesthesia. The maximum packing time is 24 hours, at which time the packing should be removed and bleeding re-evaluated.3 An umbrella packing can be used to compress bleeders in the pelvis after a hysterectomy has been performed, when there is continued bleeding. Temporary vascular occlusion is used to control bleeding awaiting completion of a more definitive procedure. Rubbershod Kelley clamps are made by inserting the proximal two inches of a red rubber catheter onto the clamps of a Kelley clamp, making it atraumatic. These can be applied atraumatically across utero-ovarian and uterine vessels to control bleeding. In massive hemorrhage, the distal aorta can be compressed above the bifurcation by placing a moist lap towel in this area and gently applying pressure. This should never be done without alerting anesthesia to manage the changes in blood pressure! Arterial ligation decreases perfusion, lowers pulse pressure, and helps control bleeding.1 The uterine, utero-ovarian, and hypogastric vessels can be ligated. It is possible to ligate any three of the four uterine and utero-ovarian vessels without compromising the uterus and future fertility. It is imperative that absorbable sutures be used. O’Leary-O’Leary ligation of the uterine arteries has almost replaced hypogastric artery ligation, because it is technically easier, quicker to perform, the vessels are easier to access, and the complications are much less. In an O’Leary-O’Leary ligation, a large absorbable suture is placed through the broad ligament lateral to the uterine vessel and into the myometrium posteriorly, then medial to the uterine vessel and tied anteriorly. For control of bleeding in uterine atony, one is placed just above the cervix bilaterally. If bleeding is from a laceration of the uterine vessel, a similar stitch is placed both above and below the laceration. Hypogastric or internal iliac artery ligation is an old procedure that is uncommonly performed by general OB/GYNs today.5 Other specialties, such as GYN, oncology, urology and vascular surgery, regularly perform the procedure. It has almost been replaced by O’Leary-O’Leary ligations as described above. Unfortunately, hypogastric artery ligation is

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

rarely taught in OB/GYN training programs today. The anterior branch of both hypogastric arteries is ligated to reduce pulse pressure and help control bleeding. This procedure is recommended only if the surgeon has the skill and expertise to complete the procedure. This is not the time to try the procedure for the first time! There is significant risk of complications! The ureter crosses the bifurcation near the point of ligation and is at risk for injury. Nerves entrapped in the ligature can cause neurologic defects. Ligation of the posterior branch of the hypogastric artery instead of the anterior causes ischemia of the buttocks. During residency training OB/GYN residents are told that, if the posterior branch is ligated, the buttocks will fall off. Ligation of the external iliac artery will cause diminished blood supply and ischemia to the lower extremity. Compression sutures have been used to compress uterine vasculature and the myometrium to control bleeding with absorbable sutures.1 In 1997 Christopher B-Lynch described brace sutures anchored anteriorly and posteriorly and extending over the top of the uterus to compress blood vessels to control bleeding.1 These have become known as B-Lynch sutures or B-Lynch brace sutures.1 Over-sewing a bleeding site or implantation site may also be useful.1 Multiple square knot sutures in the myometrium are a variation of B-Lynch sutures to control bleeding.1 Segmental resection of a portion of the bleeding myometrial wall has been described.6 The site of bleeding or of an abnormally adherent placenta can be excised, and the defect closed as in a myomectomy.6 Selective arterial embolization may be used when there are isolated bleeders causing hemorrhage, usually postoperatively. Pelvic angiography is used to visualize the bleeding vessels and place gelfoam pledgets to occlude the vessels and stop the bleeding.1 The success rate is good when there are isolated bleeders.1 The procedure requires an interventional radiologist and is limited by widespread availability. When successful, it may prevent opening or re-opening the abdomen.1 On many occasions when the abdomen is re-opened after a laparotomy or cesarean section, bleeding sites cannot be found. In these cases, angiography may help identify bleeding sites. Cesarean hysterectomy is the time-honored definitive procedure to control postpartum hemorrhage when all more conservative measures have failed. It is usually performed as a supracervical hysterectomy but occasionally as a total abdominal hysterectomy, particularly when bleeding involves the cervix or lower uterine segment. When the decision to perform a hysterectomy is made, usually there has already been excessive bleeding. The procedure is performed as an emergency under adverse conditions and carries with it an average blood loss of 2,000 ccs to 3,000 ccs. Usually, the procedure is performed as a life-saving, last-resort procedure that permanently ends fertility.

The procedure requires skill, speed, and dexterity. Only older OB/GYNs have experience with cesarean hysterectomy today. Cesarean hysterectomy is usually not taught in training programs today, and most new graduates have never seen one, much less had any experience with it. Family physicians that practice obstetrics rely on OB/GYNs when a cesarean hysterectomy is needed, yet new OB/GYNs do not have experience with it. A fairly simple technique for cesarean hysterectomy for obstetrician/gynecologists and family physicians practicing obstetrics has been recently published in the American Journal of Clinical Medicine®.7

Summary Postpartum hemorrhage is a life-threatening emergency that is a common cause of maternal mortality if left untreated. It is important to recognize when the basic maneuvers to control bleeding have failed and to get help and alert assistants, the nursing service, anesthesia, blood bank, and the operating room. Know what you are comfortable with and have a plan if the worst should happen. Keep in mind what help is available. Keep a hysterectomy instrument tray, including sutures, in the cesarean section operating room or at least in labor and delivery. Keep the patient and/or spouse and family informed. Know who to call if a cesarean hysterectomy becomes necessary. Daniel M. Avery, Jr., MD, FAASS, is Professor and Chairman, OB/GYN Department at The University of Alabama School of Medicine. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The author has stated that no such relationships exist. ®

References 1.

Foley MR, Strong TH, Garite TJ. Obstetric Intensive Care Manual. New York: McGraw Hill Co., Inc. 2004.

Baskett TF. Essential Management of Obstetric Emergencies. 3rd Edition. Bristol: Clinical Press Limited. 1999.

Quennan JT. Managing OB/GYN Emergencies. 2nd Edition. New Jersey: Medical Economics Cp. 1983.

Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap LC, Wenstrom KD. Williams Obstetrics. 22nd Edition. New York. McGraw Hill Co., Inc. 2005.

Mukhopadhyay P, Naskar T, Hazra S, Bhattacharya D. Emergency Internal Iliac Artery Ligation—Still a Life Saving Procedure. J Obstet Gynecol India. 2005;55(2):144-145.

Kayem G, Deis S, Estrade S. Conservative Management of a Near Term Cervico-Isthmic Pregnancy, Followed by a Successful Pregnancy: A case report. Fertil Steril. 2008:89(6):1826.e13-15.

Avery DM, Hooper DE, Waits JB. Cesarean Hysterectomy for Family Medicine Physicians Practicing Obstetrics. Am J Clin Med. 2009;6(2):68-71.

Review of Medical and Surgical Management of Postpartum Hemorrhage

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Transfuse or Not to Transfuse: For Post-op Anemia Jasmine Chao, DO, MS, FAAFP

Abstract An estimated five million patients receive blood transfusion per year, and blood transfusion is the most commonly employed procedure code used among inpatient stay. About 60-70% of blood transfusions take place in surgical settings.1 Although these statistics are impressive, the presence of postanemia presents a challenge for both medical and surgical specialties. In my practice, I have always tried to follow what is considered the best practice with our current understanding of the most recent research. It would be beneficial for both specialties to discuss their different points of views and expectations on this subject to achieve better patient outcome. In order to arrive at a consensus between medical and surgical specialties, I would like to review a few key publications, including the old practice guideline published by the American Society of Anesthesiologists in 2006 and the Canadian TRICC study published in 1999 in the NEJM, and compare these with the results from the much anticipated FOCUS study, which started in 2006, for hip fracture patients with cardiovascular disease or cardiovascular risk factors. These reviews compare different approaches in treating post-op surgical patients, such as a liberal red blood cell (RBC) transfusion strategy and aggressively treat moderate anemia, and their clinical outcomes.

Introduction I first became interested in this subject because of orthopedics admissions to skilled nursing facilities. I always seek to strike a balance between offering the best care and producing the best clinical outcomes in a nursing setting. However, not all admissions come with all of the most desirable criteria and potential to reach good clinical outcomes. In one recent call, I was asked

to accept a patient with hemoglobin 8.1, who just had a knee replacement done. There was no report on the discharge condition; I requested that the orthopedic surgeon ask for a medical consult for medical clearance before sending the patient out of hospital. The call back response was: The patient’s hemoglobin improved to 8.6 and he would be on his way to the nursing home by supper time.

The Lowest Safe Level of Hemoglobin In a retrospective cohort study published by Carson et al. in 2002, they looked at about 2,000 female, post-op patients, with an average age of 57 years old. Only 300 people out of 2,083 had hemoglobin lower than 8.0 who qualified for the study. When hemoglobin level decreased to 7.1-8.0 g/dL, there was no report of death, but 9.4% of cases of morbidity were reported. On the other hand, when hemoglobin level decreased to 4.1-5 g/dL, more serious consequences were encountered: 34.4% of the 300 patients died and a much higher percentage (57.5%) of patients experienced morbidity. The risk of death was low in patients with postoperative hemoglobin levels of 7.1 to 8.0 g/dL, although morbidity occurred in 9.4%. As postoperative blood counts fall, the risk of mortality and/or morbidity rises and becomes extremely high below 4 to 5 g/dL.2

Benefits of Higher Hemoglobin in Post-op Patients Would post-op patients receive any benefit from higher hemoglobin levels? A study published by Lawrence et al. in 2003 said, “They do.” Two major benefits were observed in post-op orthopedic patients. One is better functional status: they seem to walk better! It was felt that a patient’s ability to walk without

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

assistance 60 days post op correlated with success of surgery and survival. Secondly, patients seemed to have higher efficacy of rehabilitation. For example, they have shorter length of stay.3

Practice Guideline 2006 American Society of Anesthesiologists Recommendations made by the practice guideline published by the American Society of Anesthesiology in 2006 include these points. Both anesthesiologists and surgeons can have inputs on this. It describes doing a visual check in order to quickly assess blood loss. It was also felt that hemoglobin less than 6.0 g/dL is a strong indication for transfusion. There should be no blood transfusion if hemoglobin is higher than 10.0. For between 6.0 to 10.0 g/dL, it is based upon the best clinical judgments, such as evidence of organ ischemia, bleeding, intravascular volume, and patients’ own risk factors, which can predispose patients to have low cardiopulmonary reserve and high O2 consumption.4 In order to arrive at a decision on blood transfusion, you may also consider the use of the safe allowable blood loss. That is, the average blood volume that a patient may lose and still maintain hemoglobin at a safe level is about 25% of hemoglobin drop from baseline.5 This recommended 25% threshold can actually result in numbers that are higher than most physicians expect. For example, a 25% loss of a start hemoglobin 13.0 g/ dL would be as high as 9.75; a 25% loss of hemoglobin 12.0 g/ dL would be as high as 9.0. My patient’s initial hemoglobin was 11.5 and with a drop down to 8.1 g/dL, which is actually equivalent to a 30% hemoglobin loss. Even though his hemoglobin level was well above 6.0, it was still more than a 25 % drop. He could have been a good candidate for blood transfusion; however, he did not receive it in the hospital.

This trial studied two different strategies for blood transfusion: a restrictive approach and a liberal approach. In the restrictive group, patients only received blood transfusions when hemoglobin dropped below 7.0 g/dL and was maintained between 7.0 to 9.0 g/dL. On the other hand, in the liberal group, patients would always get blood when hemoglobin dropped below 10.0 g/dL and was maintained at much higher level 10.0 to 12.0 g/ dL. About 838 post-op patients were initially included, which is relevant to our discussion. The results of the study described later were based upon the entire population. In the restrictive group, 164 patients out of 418 post-op patients were qualified to enroll in the study, whereas 141 out of 420 post-op patients were selected for the liberal group. The average hemoglobin level was between 7.5 to 8.9 g/dL, which is commonly seen in post-op settings. However, because many of the population studied have multiple medical conditions, the APACHE II score was used to categorize them. APACHE is the acronym for Acute Physiology and Chronic Health Evaluation. Patients were assessed on the day of admission to ICU. The range of scores for this test is 0 to 71. The higher score indicates more severe illness. Figure 1: 30 Days Mortality in Pts with APACHE II <20.

Serious Infections May and May Not Be Identified with Transfusion Screening There are serious infections associated with blood transfusion. Currently, major viral infections, such as HIV, hepatitis B, Hepatitis C, and West Niles virus, can be identified with transfusion screening.

Figure 2: 30 Days Mortality in Pts < 55 YO.

However, there are other types of infections that are not identified with transfusion screening. These include CMV, EBV, B19 parovirus, dengue fever, Chikungunya, human herpes virus-8, and malaria, etc.6 In some cases, patients have consciously refused transfusions, either for moral, religious, or other personal reasons.

Strategy for Transfusion The Transfusion Requirement in Critical Care (TRICC) trial was the largest blood transfusion study in the past 11 years. The TRICC trial conclusions were that most ICU patients benefit from blood transfusion only if hemoglobin is less than 7.0 g/dL. A restrictive approach is more superior to a liberal transfusion approach.7

For patients with APACHE II score less than 20, the 30-day mortality rate was much lower in the restrictive group at 8.70 % compared with 16.10 % in liberal group.

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The same trend was seen in the group of patients who were younger than 55 years old; less mortality was seen in the restrictive group. Namely, only to give blood transfusion when hemoglobin drops below 7.0 g/dL and maintained between 7.0 to 9.0 g/dL. In trauma patients, the result was the opposite. A higher mortality rate was observed in the restrictive group. A very important finding emerged: patients with clinically significant cardiac diseases showed no clear distinction between the restrictive versus the liberal approach. Figure 3: 30 Day Mortality in Pts with Trauma.

Rao et al. reported that in patients with acute coronary syndrome who received transfusion there was an increase in mortality risk.9

Blood Transfusion Strategy on Patients With Cardiovascular Diseases or Risks Factors Transfusion trigger trial for Functional Outcomes in Cardiovascular patients Undergoing Surgical (FOCUS) hip fracture repair is to determine clinical outcomes in patients with cardiovascular diseases or cardiovascular risk factors using more aggressive transfusion strategy.10 The results of the study, which began in 2006 and is still ongoing, have not been finalized. The study followed 2,016 patients, age ranging from 51 to 103, with average age 81.6 years old, who underwent hip fracture repair surgery. It took place at 47 medical centers in the United States and Canada between August 2004 and February 2009. The elderly patients either had cardiovascular disease or were at high risk for it. It is a randomized, un-blinded, parallel, two groups, and multicenter trial. The exclusion criteria are the following:

Figure 4: 30 Days Mortality in Pts with Clinically Significant Cardiac Diseases.

•

Unable to walk without human assistance postop hip fracture repair

•

No blood transfusion

•

Multiple trauma

•

H/o malignancy and pathological fracture

•

Previous trial participant

•

Active chest pain (cardiac)

•

Active bleeding

•

Fractures of greater and lesser trochanters

The definitions for cardiovascular disease included in this study are: 1. 2. 3. 4. 5. In the TRICC trial, more episodes of MI, pulmonary edema, and slightly longer hospital stay were observed in the liberal transfusion group. The conclusion of the TRICC is that blood transfusion is indicated in hemoglobin < 7.0 g/dL for ICU patients. Perhaps it can be said that a restrictive approach is superior to keeping hemoglobin >10.0 g/dL (liberal approach) except for patients with significant cardiac disease. In addition to the 2006 practice guideline from ASA and since the TRICC trial, there have been other published studies with conflicting results. One study published in the NEJM in 2001 suggested patients with MIs should receive blood transfusion if hematocrit level falls below 33%.8

H/o MI EKG changes c/w old MI CHF PAD CVA

6. TIA The definitions for cardiovascular risk factors included in this study are:

•

HTN DM Dyslipidemia (LDL >130, total cholesterol >200) Tobacco use

•

Creatinin > 2.0

• • •

All the patients had hemoglobin levels <10.0 g/dL three days after post-op hip fracture treatment.10

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

In the group of symptomatic transfusion, if patients complained of symptoms such as chest pain that is cardiac in nature, CHF, tachycardia, hypotension, volume depletion not responding to fluid, they would receive blood transfusion if hemoglobin <8.0 g/dL. In the liberal group, patients would receive one unit of PRBC and more transfusions to keep above 10.0 g/dL. The primary goal was the improved ability to walk 10 feet across the room without human assistance 60 days after surgery. The secondary goal was to investigate the risk of post-op MI or death, the risk of 30 days post-op mortality, improvement at 30 days, 60 days LE function of IADL, and patients remaining in SNF > 60 days post-op. The last goal was to investigate risks post-op in-patient non-infectious morbidity, such as delirium, stroke, thrombo-embolism, risks post-op pneumonia, 30 days composite outcomes (MI, pneumonia, stroke and thrombo-embolism), medical errors, and characteristics for successful rehabilitation. For the results with secondary aim, the stand-alone rate of in-hospital mortality, 2% for the liberal group versus 1.4% symptomatic group, were observed, which failed to reach statistical significance. According to Dr. Carson, who reported at the American Heart Association Scientific Sessions in November 2009, “Many clinicians base their decisions only on the hemoglobin levels. This trial seems to say that you need to look at every patient individually, to evaluate their symptoms. The overall interpretation of the trial will depend on consideration of functional outcomes, infection outcomes, and longer-term mortality. Only after consideration of all these outcomes can the clinician fully weigh the pros and cons of the different transfusion methods.”11

Jasmine Chao, DO, MS, FAAFP, is board certified in both family practice and geriatric medicine. She is a solo practitioner in a suburb of Chicago and currently is an associate staff member at Northshore University Healthcare System and Resurrection Healthcare. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The author has stated that no such relationships exist. ®

References 1.

C. Hillyer et al. Transfusion recipient epidemiology and outcomes research: possibilities for the future. Transfusion. August 2008;Vol 28.

Carson et al. Mortality and morbidity in patients with very low post-op Hb levels who declined blood transfusion. Transfusion. 2002;Vol 42:812-818.

Lawrence et al. High hemoglobin level is associated with better early fracture after hip repair. Transfusion. 2003;Vol 43:1717.

Practice guidelines for peri-operative blood transfusion and adjuvant therapies. Anesthesiology. July 2006;Vol 105:198-208.

Lane et al. Blood Management for Hip Reconstruction Surgery. Orthopedic Clinics of North America. July 2009;Vol 40, 3.

Hillyer et al. Transfusion recipient epidemiology and outcomes research: possibilities for the future. Transfusion. August 2008;Vol 48.

Paul C Hebert et al. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirement in Critical Care (TRICC). NEJM. February 1999;Vol 340, 6.

Wu et al. Blood transfusion in elderly patients with acute MI. NEJM. 2001;Vol 345:1230-1236.

Rao et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004;Vol 292:1555-1562.

10. Carson et al. Transfusion. Dec 2006;Vol 46. 11. Carson J. LBCT02 # 116. Presented at: American Heart Association Scientific Sessions. Nov. 14-18, 2009; Orlando.

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

A Critical Appraisal of the Evolution of ST Elevation Myocardial Infarction (STEMI) Therapy and the Evidence Behind the Current Treatment Guidelines Leslie Mukau, MD, FAAEP, FACEP

Abstract In the United States cardiovascular disease is the leading cause of and is responsible for 26% of deaths each year. Half of the deaths due to heart disease in 2006 were women. In 2009, the Center for Disease Control (CDC) estimated that 785,000 Americans had a new myocardial infarction and about 470,000 had a recurrent attack. Nearly 400,000 Americans will die of CHD in 2010. The cost of heart disease in terms of health care services, medications, and lost productivity for 2010 has been estimated at $316.4 billion. The current therapeutic guidelines for the treatment of ST elevation myocardial infarction are reviewed from a historical perspective, and the scientific evidence behind such guidelines is systematically analyzed.

Prevalence and Scope of the Problem In the United States cardiovascular disease has been the leading cause of death every year since 1900, except 1918, the year of the Spanish flu epidemic, and is responsible for 26% of deaths each year. Half of the deaths due to heart disease in 2006 were women. In 2009, the Center for Disease Control (CDC) estimated that 785,000 Americans had a new myocardial infarction, and about 470,000 had a recurrent attack. Nearly 400,000 Americans will die of CHD in 2010.1-4 The cost of heart disease in terms of health care services, medications, and lost productivity for 2010 has been estimated at $316.4 billion.2 The risk factors for coronary disease have been mapped out (5) and about 37% of American adults report two or more of these risk factors.6 While heart disease is usually thought of as malediction of advanced societies and modern lifestyles, recent multidisciplinary studies of mummified remains have provided

evidence of this particular phenotype among some elite classes of ancient Egyptians.7-11

Brief Historical Synopsis Setting the Stage Although William Heberden coined the term angina pectoris in 1768,12 myocardial infarction remained mostly a medical curiosity until towards the end of the nineteenth century. For more than a hundred years after Heberden’s clinical finding, the pathophysiology of acute myocardial infarction remained elusive until the German pathologist Carl Weigert in 1880 clearly correlated myocardial infarction as a disease of the coronary arteries and exhibiting specific myocardial changes.13 William Osler14 and George Dock15 started teaching this possible clinical link. By 1910 two Russian clinicians, Obraztsov and Strazhesko, actually documented clinical features of myocardial infarction in a living patient.16 However the evolution of modern day understanding and treatment of myocardial infarction began with James B. Herrick. In a landmark presentation to the Association of American Physicians in 1912, he coherently introduced the classic signs and symptoms of acute coronary artery occlusion.17 Although that presentation is now universally hailed as the burgeoning of the clinical and pathophysiologic basis of coronary artery syndrome, it was met with indifference by his peers. Years later Herrick would reminisce, “My paper on the diagnosis of coronary thrombosis during life rather than only at autopsy, which I presented at the 19122 meeting of the Association of American Physicians, fell like a dud.” In 1918 James Herrick was one of the first to encourage electrocardiography, which had been created by Einthoven in 1902, in the

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

diagnosis of myocardial infarction and has continued to be an indispensible major diagnostic tool for acute myocardial infarction up to the present time. Herrick also advocated bed rest as mainstay therapy for myocardial infarction. Bed rest was the only therapeutic option available at that time. Patients were essentially bedridden for up to six weeks and were not allowed to move or to feed themselves during the first post infarction week.18, 19 This practice became established as a prime therapeutic cornerstone for the next 50 years. The first clinical series of 19 patients with myocardial infarction by Wearn20 appeared in the literature in 1923. By 1928, Parkinson and Bedford reported their series of 100 patients with acute myocardial infarction and detailed their experience with the use of morphine to relieve pain but advised against the use of nitrates because of the potential for hypotension.21 A year later Samuel Levine in another series of 145 acute myocardial infarction patients noted the frequency and risk of various cardiac dysrhythmias and advocated the use of quinidine to treat ventricular tachycardia and intramuscular adrenaline for heart block and syncope. He further suggested that nurses be trained to use a stethoscope “to follow carefully the rate and rhythm of the apex beat,” so that the dysrhythmias could be treated promptly even when a doctor was not present. This suggestion was at least three decades ahead of the arrival of coronary care units.22 Levine and Lown also proposed “armchair treatment” of AMI in 1952 but were met with resistance and heated debate.23 During the 1950s, the therapy of myocardial infarction included the administration of oxygen (in the presence of shortness of breath [rales] and cyanosis) and intravenous fluids (to prevent dehydration) as popularized by Tinsley Harrison, the founding editor and editor-in-chief of the first five editions of Harrison’s Principles of Internal Medicine.24 Subcutaneous atropine and papaverine, followed by sublingual nitroglycerine (glyceryl trinitrate) were routinely used to prevent or relieve coronary spasm. By 1920 it had become accepted by most that sudden occlusion of the coronary artery was the trigger for myocardial infarction. When the anticoagulants heparin and bishydroxy-coumarin (Dicumarol) were developed in the 1930s, they were adopted for use in treating AMI. In a report of 800 patients in 1948 Irving Wright advocated the use of anticoagulants in myocardial infarction to prevent reinfarction, mural thrombus, and pulmonary embolism.25 These treatment modalities reigned supreme for many decades.

Arrival of the Main Pharmacological Characters The latter half of the twentieth century brought reports that daily, low doses of aspirin appeared to be antithrombotic and could help prevent myocardial infarction and stroke. This finding was first reported by Lawrence Craven, a suburban general practitioner in Glendale, California. In 1950 Craven hypothesized that aspirin was preventive of coronary thrombosis. He cited evidence that aspirin prolonged prothrombin time. He also cited reports of more frequent hemorrhaging among patients who chewed aspirin gum after a tonsillectomy or a tooth extraction.

Craven then prescribed daily aspirin to 400 patients in 1948, and he reported in 1950 that none had suffered a myocardial infarction during that two-year period.26, 27, 28 Unfortunately, Craven’s work languished in obscurity, and it would be decades before his observations would be validated by clinical trials. Aspirin would play a large role and would be a cornerstone in antiplatelet therapy for acute myocardial infarction. In 1933, while conducting an experiment at the Johns Hopkins Institutes Tillet and Garner accidentally found that Lancefield Group A beta-hemolytic streptococci were capable of producing a fibrinolytic substance, later named streptokinase.29 Shortly thereafter Christiansen and MacLeod showed that this streptokinase could convert plasminogen to the proteolytic and fibrinolytic enzyme plasmin, which, in turn, was capable of degrading fibrinogen and fibrin. By 1947, Christiansen provided Tillet, Sherry, Hazelhurst, and Johnson with a crude preparation of streptokinase, which they used clinically to treat hemothorax, empyema, and abscess cavities with great success.30, 31 Then Tillet and Johnson in 1952 reported lysing of experimental thrombi in rabbits’ ears with streptokinase administered intravenously through a peripheral vein.32 Once purified preparations of streptokinase were made available by Lederle Laboratories five years later in 1957, Sherry’s group proposed a rational clinical strategy for intravenous fibrinolysis involving a loading dose of streptokinase, followed by a continuous infusion sufficient to maintain a plasma streptokinase concentration of about 10 μg/mL.33 This proposal was subsequently followed by the first human study of intravenously administered streptokinase for the treatment of AMI.34 Even at that time, interestingly enough, it was noted that the early administration of streptokinase (within 14 hours of symptom onset) resulted in low in-hospital mortality compared to those patients with delayed treatment whose in-hospital mortality was similar to untreated patients. However, the pathophysiological recognition of the open-artery hypothesis and the consequential universal adoption of thrombolytic agents as primary treatment of AMI would be delayed for decades because of a heated controversy over the exact role played by coronary thrombosis in the pathogenesis of AMI.

The Great Pathological Debate and the Dawn of a New Era It is a strange twist of events in that while developments in thrombolytic therapy were beginning, a highly heated and voluble debate was brewing at the same time about the exact role coronary thrombosis played in the events leading to AMI. In 1939 Charles Friedberg and Henry Horn, pathologists from the Mount Sinai Hospital in New York, published an article in JAMA entitled, “Acute myocardial infarction not due to coronary obstruction.” In their paper these authors argued that evidence of coronary thrombosis was only present in 31% of patients who had evidence of myocardial necrosis on autopsy.35 Studies by other pathologists36-40 appeared to collaborate this finding and called into question the cause-and-effect relationship between coronary thrombosis and AMI. The argument posed by these

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anatomical pathologists was that if coronary thrombosis were the cause of myocardial infarction, it should be evident in virtually all the cases. The most significant and vocal proponent of this argument was William C. Roberts, the Section Chief of the Cardiac Pathology Heart Institute at the National Institutes of Health. He vehemently believed that coronary thrombosis was the result, rather than the cause, of myocardial necrosis: “Although it may play a major role in causing atherosclerosis, coronary thrombosis may well play a minor role or none at all, in precipitating a fatal coronary event… Evidence [has been] gathered suggesting that myocardial necrosis comes first and that coronary thrombosis is secondary.”41 Within a few years Roberts and his cohorts had a resounding rebuttal to their hypothesis by Marcus DeWood and his colleagues from Spokane, Washington. In 1980, DeWood et al. published a landmark paper in the New England Journal of Medicine that grabbed the attention of everyone remotely involved in cardiac care.42 After recognizing the inherent limitations of autopsy series in the study of AMI Pathophysiology, these researchers decided to perform coronary angiography in live patients within 24 hours of presentation with AMI. At that time this was indeed a revolutionary concept, since the perceived wisdom of the time was that injection of contrast media during AMI would inevitably result in fatal arrhythmia or hemodynamic compromise during the procedure. This study showed total coronary occlusion in 110 out of 126 patients (87%) presenting within four hours of the onset of symptoms suggestive of AMI. Thrombus was demonstrated angiographically in 59 patients. In addition DeWood was able to retrieve the thrombus in 52 (88%) of these patients using a Fogarty catheter. Finally, the debate was settled in favor of the “open artery hypothesis” and laid down the foundation and convincing argument for thrombolysis and percutaneous coronary intervention for the treatment of ST elevation myocardial infarction.

Decreasing Mortality from Acute Coronary Syndrome In the past few decades mortality from acute coronary syndrome in the United States has been decreasing43-46 (Table 1). Approximately 47% of the decrease in mortality has been attributed to therapeutic interventions and 44% to changes in the major risk factors for heart disease.47 Studies from other countries have collaborated this welcome trend.48-55 One of the major innovations that brought down in-hospital mortality of AMI was the development of Coronary Care Units in the early sixties. Although Samuel Levine, as we have seen before, encouraged the treatment of cardiac dysrhythmias related to myocardial infarction and advocated the training of nurses to recognize such, his idea was not fully considered until the advent of coronary care units in the sixties. The very first description of the coronary care unit (CCU) was presented to the British Thoracic Society in July 1961 by Desmond Julian.56 Within the year these units had spread all over the world.57 The technique of closed-chest cardiopulmonary resuscitation

by Kouwenhoven, Jude, and Knickerbocker in 1960 at Johns Hopkins58 and the adoption of a continuous telemetry monitoring system with an alarm,57 laid the groundwork for coronary care units. To complete these developments patients with AMIs were clustered in a single hospital unit where trained personnel were in continuous attendance and where necessary equipment and drugs were also readily available. The training of specialized nurses to recognize and treat arrhythmias rapidly in the absence of a physician59 revolutionized treatment in these units. By 1967 Killip and Kimball published their series of 250 patients with AMIs who had been treated in the CCU. Compared with other patients who had experienced AMIs, those treated in the CCU had better survival rates in the absence of cardiogenic shock.60 Similar results were reported from other centers. The introduction of CCUs reduced the mortality rate of AMI from 30% to 15%.61, 62, 63 Table 1: Decreasing mortality of Acute Coronary Syndrome with time.

Pathophysiology of STEMI Acute coronary syndrome consists of a spectrum of clinical conditions ranging from unstable angina, non-ST elevation MI (non-Q wave), and ST elevation MI (Q wave). All these conditions are characterized by the common pathophysiology of a disrupted atherosclerotic plaque (Figures 1 and 2). In the majority of cases the syndrome occurs when an atherosclerotic plaque ruptures, fissures, or ulcerates and precipitates thrombus formation, resulting in an acute total or near-total arterial occlusion. Alternatively, a piece of thrombus may break off leading to downstream vessel occlusion. Platelets play a central role in the development of thrombi and subsequent ischemic events, and this process of platelet-mediated thrombus formation involves adhesion, activation, and aggregation. Plaque rupture exposes subendothelial collagen, a highly thrombogenic material, which serves as a site of platelet adhesion, activation, and aggregation. Activated platelets undergo a series of steps including: shape change, adhesion to endothelial cells of vessels, aggregation, and the secretion of granules that perpetuate the cycle.64, 65, 66 Fibrinogen and thrombospondin are secreted from a-granules. Within one minute

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of activation, the presence of fibrinogen and thrombospondin results in platelet aggregation through the linking of glycoprotein (GP) IIb/IIIa complexes.65 An adhesive glycoprotein, von Willebrand factor (vWF), allows platelets to stay attached to the subendothelial vessel wall (via GP Ib) despite high shear forces. Following adhesion, platelets are activated to secrete a variety of agonists which are pro-aggregatory molecules, such as thrombin, serotonin, adenosine diphosphate (ADP), and thromboxane A2 (TXA2) (Figure 3). These agonists, which further augment the platelet activation process, bind to specific receptor sites on the platelets to activate the GP IIb/IIIa receptor complex, the final common pathway to platelet aggregation.67, 68 Once activated, the GP IIb/IIIa receptor undergoes a conformational change that enables it to bind with fibrinogen (Figure 5). The shape of platelets changes from a discoid to spherical within seconds after activation once the concentration of ADP approaches 2–5 µM.69,70 ADP binds to specific ADP receptors located on the platelet membrane including P2Y1, P2Y12 and P2X1.66 Therefore, ADP is considered a natural agonist of platelet aggregation, as this molecule is involved in a positive feedback mechanism potentiating the process of platelet activation and thrombus formation. This role of ADP and ADP receptors as we will see has tremendous therapeutic implications and has been the subject of intensive research in the past three decades.

size encompassing the entire area at risk.71 This concept of Reimer and Jennings is fundamental to current revascularization therapy of acute ST-elevation myocardial infarcts (STEMI).72 Indeed, modern therapeutic modalities for STEMI aimed at opening the infarct-related artery as quickly as possible in order to reduce the duration of ischemia and to save viable myocardium in the risk area are predicated on this concept.

Figure 1: The spectrum of Acute Coronary Syndrome.

Figure 3: Atherosclerotic Plaque Disruption and Platelet Activation.

Reimer and Jennings, in the 1970s, performed a series of experimental studies in dogs after acute coronary occlusion, in which they examined the relation between duration of ischemia, area at risk, collateral blood flow, and final infarct size. Their results introduced the concept of “wave front phenomenon of myocardial death.” This concept states that infarct size increases in a transmural wave front extending from the endocardium to the epicardium with increasing duration of coronary occlusions and with increasing severity of ischemia. Coronary occlusions lasting < 6 hours result in subendocardial infarcts, in which infarct size is smaller than the ischemic area at risk, because some epicardial rim of viable tissue is spared. When coronary occlusion exceeds six hours, infarcts become transmural with an infarct

Figure 2: Features and Characteristics of Acute Coronary Syndrome.

The disruption of an atherosclerotic plaque results in exposure of highly thrombogenic material. In patients with atherothrombosis, the activation of platelets and coagulation are inseparable, reciprocally self-amplifying processes. The inhibition of platelets alone does not block the coagulation activators. GP denotes glycoprotein, ADP adenosine diphosphate, and COX-1 cyclooxygenase-1. Adapted after Mohler E R. N Engl J Med. 2007;357:293-296.

Progression of postinfarct myocardial pathology can lead to the occurrence of possible characteristic complications at predictable times after the initial event. While there may be no apparent visible alterations in the gross morphological appearance of infarcted tissue for at least six hours after the onset of cell death, changes in cell biochemistry and ultrastructure begin to show abnormalities within 20 minutes of ischemia. Myocardial ischemia can cause an immediate loss of contractility in the affected myocardium, leading to hypokinesis. After about 15–30 minutes of sustained coronary occlusion, necrosis starts to develop in the subendocardium, with the necrotic region marching outward towards the epicardium within the next three to

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six hours, eventually spanning the entire ventricular wall. In some areas (generally at the edges of the infarct) the myocardium is stunned (reversibly damaged) and can eventually recover if blood flow is restored. Contractility in the remaining viable myocardium increases, a process termed hyperkinesis. Cell damage is progressive, becomingly increasingly irreversible over about 12 hours. Therefore, this period can provide a window of opportunity during which thrombolysis and reperfusion may salvage some of the infarct. Between four and twelve hours after cell death starts, the infarcted myocardium begins to undergo coagulation necrosis, a process characterized by cell swelling, organelle breakdown, and protein denaturation. Between four and seven days following a STEMI the infarcted myocardium is especially soft and prone to rupturing, an event usually fatal, and can occur at any time during the initial first two weeks and is responsible for about 10% of STEMI mortality. By about two to three months following the infarction, the area has healed, leaving a thinned, firm and pale grey noncontracting region of the ventricular wall. Over the course of several months, there is progressive dilatation, not only of the infarct zone, but also of healthy myocardium. This process of ventricular remodeling is caused by an increase in end-diastolic wall stress. Infarct expansion puts patients at a substantial risk for the development of congestive heart failure, ventricular arrhythmias, and free wall rupture.

The Randomized Mega Trials and the Thrombolytic Era In the 1970s, mortality rates for patients hospitalized with AMI ranged from 10% to 45% among different institutions.73 Early attempts at using thrombolytic therapy for STEMI showed mixed results.74-77 Rentrop demonstrated that local intracoronary infusion of streptokinase into the infarct artery could promptly recanalize the vessel and reestablish flow.78 Anecdotal observations consistently found a high rate of spontaneous recanalization, but most often were too little, or appeared too late. In 1983 Schroder introduced and demonstrated the efficacy of a high-dose bolus intravenous infusion of streptokinase in achieving early recanalization of the infarct vessel.79,80 Albeit the use of streptokinase appeared favorable, decisive conclusions appeared lacking because most of these series suffered from inadequate sample size or were performed in nonrandomized patient populations. In addition there were no universal protocols established at this time. By the early eighties a number of small series attempting to standardize a protocol ended up showing that improved reperfusion rates and better left ventricular function were dependent on time interval between onset of symptoms and streptokinase infusion, especially if streptokinase was administered early within one and one-half to three hours.81-91 Finally in 1986, a landmark study, GISSI-1 (First study of the Gruppo Italiano per lo studio della strepochinasi ell’ infarto Miocardio) became the first large randomized international trial to convincingly and definitively show that intravenous thrombolytic therapy with streptokinase improved survival.92 The

objective of the trial was to evaluate the efficacy of a thrombolytic treatment with streptokinase (SK) on in-hospital mortality of patients with acute myocardial infarction (AMI). It was an open controlled clinical trial with central randomization of 11,712 patients to SK or control group of patients with AMI admitted within 12 hours from the onset of symptoms. Thrombolytic treatment significantly reduced mortality among patients treated with SK compared to controls, receiving conventional treatments: 10.7% SK vs. 13% controls, for an 18% reduction (p=.0002). The difference in survival produced by streptokinase and sustained up to one year was still significant at 10 years (log-rank test: p=0.02) with the absolute benefit of 19 lives saved per 1000 patients treated. The GISSI-1 report was soon followed by a randomization of more than 100,000 patients in three large-scale trials directly comparing different thrombolytic agents. GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries),93 GISSI -2 (Gruppo Italiano per so Studio della Sopravvienza nell’Infarto Miocardico),94, 95 and ISIS-3 (Third International Study of Infarct Survival Collaborative Group).96 These mega trials conclusively established the validity of the “open artery hypothesis” by demonstrating that opening up an occluded coronary artery within 90 minutes after treatment with intravenous thrombolytics resulted in a 15% reduction in mortality. Thus the concept of short “doorto-needle” mantra became a priority in the treatment of acute STEMI internationally. Other clinically relevant conclusions from GISSI-2, ISIS-3, and GUSTO-1 were that the choice of thrombolytic therapy was much less important to ultimate survival than was the delay time between onset of symptoms and initiation of treatment. In 1990 Kareiakes et al. showed that the average in-hospital delay for patients treated with thrombolytic agents is almost 90 minutes in the United States.97 Development of local protocols in emergency departments designed to decrease this time delay have gone a long way in saving more lives. In addition all three agents appeared to be effective even when given up to 12 hours after the onset of symptoms. Indeed in the early 1990s some studies, such as EMERAS (Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur)98 and LATE (Late Assessment of Thrombolytic Efficacy)99 specifically looked at thrombolytic therapy in STEMI patients presenting six hours after the onset of symptoms. EMERAS found no significant differences in hospital mortality observed between the streptokinase and placebo groups (11.9% vs. 12.4%). The LATE (Late Assessment of Thrombolytic Efficacy) study (javascript:newshowcontent [‘active’,’references’]); showed no benefit for thrombolytic therapy in STEMI if administered 12 to 24 h after the symptoms.99 A meta-analysis of all randomized fibrinolytic trials with greater than 1000 patients was performed by the Fibrinolytic Therapy Trialist (FTT) Collaborative group in 1994. This analysis revealed that the greatest mortality benefit was achieved in the first three hours of symptom onset, especially the first hour.100 If treatment was within the first hour of symptoms, 39 lives were saved per 1000 patients treated. If treatment was within two to three hours, 30 lives were saved, while if treatment was within seven to twelve

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hours after symptom treatment, 21 lives were saved. An absolute benefit reduction of 1.6 lives was cost by each hour delay in treatment (Figure 4). Figure 4: Number of lives saved per 1000 patients treated with fibrinolytic at different treatment time delays from symptom onset.

Adapted from Terkelsen TJ, Larsen JF, Norgaard BL et al. Are we understanding the full potential of early thrombolytic treatment in patients with acute myocardial infarction? Heart. 2003;89:483-484.

The ideal fibrinolytic agent is one that would achieve 100% patency in a short time period while having minimal bleeding complications and improve microvascular function and flow. It would have a prolonged half-life and slow plasma clearance and be easy to administer as a bolus. It would also be highly fibrin specific with little or no fibrinogen depletion. In addition, it would be easier to use. The thrombolytic agents currently available, such as rPA (reteplase) and TNKtPA (tenecteplase), are more fibrin specific and easier to use compared to the first generation agents.101-105 Reteplase (r-PA) was one of the first bolus lytics and mutant variations of wild-t-PA. Tenecteplase or TNK-tPA is a deletion mutant of naturally occurring t-PA, which can be administered as a single bolus. TNK-PA is more fibrin specific than alteplase or reteplase. Lanoteplase (n-PA) is another deletion mutant of naturally occurring t-PA. The IN-TIME -2 trial (Intravenous nPA for Treatment of Infarcting Myocardium Early) was a large randomized equivalency trial testing 120KU/kg of lanoteplase with accelerated alteplase. The 30-day mortality rates were similar between the two agents, but intracranial hemorrhage was significantly higher with n-PA (1.13% vs. 0.62% p < [less than] 0.003) (106). As a result, the agent is not presently being developed for clinical use.

Antiplatelet Therapy Platelet Physiology Platelets are anucleate blood cells that form by fragmentation of megakaryocyte cytoplasm and have a maximum circulating life span of about ten days in man. Under normal physiological circumstances approximately ten11platelets are produced each day but can increase up to tenfold in times of stress and increased need. Platelets provide a circulating source of che-

mokines, cytokines, and growth factors that are preformed and packaged in storage granules. Platelet activation process involves the production of multiple activation agonists that include thrombin, thromboxane A2, and adenosine diphosphate (ADP), which amplify the platelet response and stimulate platelet aggregation. The purinergic receptors expressed on platelets consist of P2X1, P2Y1, and P2Y12. Adenosine triphosphate (ATP) is the physiological agonist of P2X1 ligand-gated cation channels involved in extracellular calcium influx and, thereby, changes in platelet shape and also helps to amplify platelet responses mediated by other agonists. ADP as a physiological agonist exerts its action on platelets through both G protein-coupled seven transmembrane domains purinergic receptors, P2Y1 and P2Y12. The activation of the P2Y1 receptor also leads to a transient change in platelet shape, intracellular calcium mobilization, granule release of other mediators and finally initiates a weak but transient phase of platelet aggregation. While both P2Y receptors are needed for complete aggregation, ADP-stimulated effects on platelets are upheld predominantly through the Gi-coupled P2Y12 receptor. Thus activation of the P2Y12 receptors causes a series of intracellular events that result in calcium mobilization, granules release, thromboxane A2 generation, and activation of glycoprotein IIb/IIIa receptor, which leads to amplification of platelet aggregation and stabilization of the platelet aggregate. As a result, platelet P2Y12 blockade is pivotal in attempting to inhibit thrombus formation by platelet activation and aggregation. As demonstrated earlier in the pathophysiology of STEMI the nidus of an occlusive coronary thrombus is the adhesion of a small collection of activated platelets at the site of intimal disruption in an unstable atherosclerotic plaque. After an atherosclerotic plaque rupture, platelet- mediated thrombosis occurs through a tri-step process involving adhesion, activation, and aggregation. Each of these three phases represents a potential target for the development of pharmacologic antiplatelet agents. Inhibitors of platelet adhesion are still under investigation and not yet approved for clinical use. Inhibitors of platelet aggregation (i.e., intravenous glycoprotein IIb/IIIa inhibitors) are reserved only for the acute phase treatment of high risk ACS patients undergoing PCI. On the other hand inhibitors of platelet activation processes represent the mainstay treatment for the acute and long-term prevention of recurrent ischemic events in ACS and PCI patients. Adenosine diphosphate stimulates platelet activation through two G-protein coupled receptors, P2Y1 and P2Y12.107 Although binding of ADP to both receptors is required for complete platelet aggregation, P2Y12 is the predominant receptor involved in ADP-stimulated platelet activation of the glycoprotein (GP) IIb/ IIIa receptor.108 Binding of ADP to P2Y1 stimulates activation of the GP IIb/IIIa receptor resulting in calcium mobilization, platelet shape change, and transient platelet aggregation.109,110 Binding of ADP to P2Y12 stimulates activation of the GP IIb/ IIIa receptor resulting in enhanced platelet degranulation and thromboxane production and prolonged platelet aggregation (Figure 5).111-113 Moreover, activated platelets can synthesize prostanoids, primarily thromboxane (TX)A2 from arachidonic

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Figure 5: Mechanisms of platelet activation and potential receptor site blockage by various anti-platelet agents.

Wallentin L. Eur Heart J. 2009;30:1964-1977

acid released from membrane phospholipids through rapid coordinated activation of phospholipase(s), cyclo-oxygenase (COX)-1 and TX-synthase. At least four distinct platelet proteins represent the target of reversible and irreversible inhibitors with variable antiplatelet effects, i.e., COX-1, glycoprotein (GP)IIb/IIIa, the PGH2/TXA2(TP) receptor and the ADP receptor P2Y12.114-118 Figure 6: Arachidonic acid metabolism via the cyclo-oxygenase (COX) pathways.

Low-dose aspirin is shown inhibiting the COX-1 pathway. This results in suppression of thromboxane (TX) A2 and prostaglandin (PG) E2 synthesis in platelets. However, the same products can be formed through the COX-2 pathway in an aspirin-insensitive fashion. PLA2, phospholipase A2; EP, PGE2receptor; IP, prostacyclin receptor; TP, thromboxane receptor.

An Aspirin a Day Biochemically aspirin induces an irreversible functional defect in platelets, detectable clinically as a prolonged bleeding time. This appears to be primarily, if not exclusively, due to permanent inactivation by aspirin of a key enzyme in platelet arachidonate metabolism (Figure 6). Prostaglandin (PG) H-synthase, produces PGH2, the precursor of thromboxane (TXA2). Thromboxane A2 is synthesized and released by platelets in response to a variety of stimuli (for example, thrombin, collagen, and adenosine diphosphate) and in turn induces irreversible platelet aggregation, 119-121 thereby providing a mechanism for amplifying the platelet response to such diverse agonists. Aspirin selectively acetylates the hydroxyl group of a single serine residue at position 529 within the polypeptide chain of platelet prostaglandin G/H synthase 1,122-124 causing the irreversible loss of its cyclooxygenase activity. This enzyme exhibits two distinct catalytic activities: a bis-oxygenase (cyclo-oxygenase [COX]) involved in formation of PGG2, and a hydroperoxidase allowing a net two-electron reduction in the 15-hydroperoxyl group of PGG2, thus yielding PGH2. Through O-acetylation of Ser529 by aspirin, the cyclo-oxygenase activity is lost permanently, whereas the hydroperoxidase activity is not affected. An inducible form of PGH-synthase has been identified and termed PGH-synthase 2 or COX-2.125 Aspirin inhibits the cyclo-oxygenase activity of PGH-synthase 2, but at higher concentrations than those required to inhibit PGH-synthase1or COX-1 (i.e., the constitutive enzyme).126 This may account, at least in part, for the different dose requirements of analgesic and anti-inflammatory versus antiplatelet effects of the drug. Normally COX-

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2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Within minutes, aspirin prevents additional platelet activation and interferes with platelet adhesion and cohesion. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group was a multicenter, multinational, randomized, double-blind, placebo-controlled randomized trial of 17,187 cases of suspected acute myocardial infarction.127 Patients were randomized to one of four groups involving streptokinase (SK) or aspirin.

ized trials randomizing STEMI patients to either low vs. high doses of aspirin in STEMI have been conducted, extrapolation from the GUSTO I and GUSTO III trials (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) 130 as well as results from non-randomized retrospective analysis of studies comparing 30-day mortality and bleeding risks associated with the administration of 162 mg versus 325 mg of aspirin among patients with STEMI treated with thrombolytic therapy shows that 162 mg of aspirin may be as effective as, and perhaps safer than, 325 mg for the acute treatment of STEMI. 131,132 Figure 7: Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and Ticagrelor.

1. SK (1.5 million U over 60 min) and aspirin (162.5 mg/ day for one month). 2. SK (1.5 million U over 60 min) and placebo matching aspirin (enteric-coated starch). 3. Placebo matching SK (Hepatitis-B-antigen-free albumin) and aspirin (162.5 mg/day for one month). 4. Placebo matching SK and placebo matching aspirin. The study results revealed that Streptokinase alone and aspirin alone each produced a highly significant reduction in five-week vascular mortality: 791/8592 (9.2%) among patients allocated streptokinase infusion vs. 1029/8595 (12.0%) among those allocated placebo infusion (odds reduction: 25% SD 4; 2p less than 0.00001); 804/8587 (9.4%) vascular deaths among patients allocated aspirin tablets vs. 1016/8600 (11.8%) among those allocated placebo tablets (odds reduction: 23% SD 4; 2p less than 0.00001) (Figure 6). The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular deaths appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents vs. 568/4300 (13.2%) among those allocated neither (odds reduction: 42% SD 5; 95% confidence limits 34-50%) (Figure 7). There was evidence of benefit from each agent even for patients treated late after pain onset (odds reductions at 0-4, 5-12, and 13-24 hours: 35% SD 6, 16% SD 7, and 21% SD 12 for streptokinase alone; 25% SD 7, 21% SD 7, and 21% SD 12 for aspirin alone; and 53% SD 8, 32% SD 9, and 38% SD 15 for the combination of streptokinase and aspirin). The early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seem to be maintained for at least ten years.128 Aspirin alone has one of the greatest impacts on the reduction of MI mortality and has become the cornerstone of treatment in both acute coronary syndromes and chronic coronary artery disease. Its beneficial effect is observed early in therapy and persists for years with continued use. The long-term benefit is sustained, even at doses as low as 75 mg/day. Some studies suggest that enteric coating may delay aspirin absorption, 129 making it preferable to give non-enteric coated aspirin in the setting of STEMI. While no large, prospective, random-

After Schömig A. N Engl J Med. 2009;361:1108-1111.

Recent reviews of a large database of randomized clinical trials133,134 provide the most compelling evidence that prevention of myocardial infarction and ischemic stroke by aspirin is largely due to permanent inactivation of platelet COX-1. By testing the efficacy and safety of aspirin at daily doses ranging from as low as 30mg to as high as 1500mg, these studies have revealed that the anti-thrombotic effect of aspirin is saturable at doses in the range of 75 to 100mg, and that despite a half-life of approximately 20 minutes in the human circulation, the antithrombotic effect of aspirin is observed with dosing intervals of 24 to 48 hours, reflecting the permanent nature of platelet COX1 inactivation and the duration of TXA2 suppression following oral dosing in man.

Adenosine Diphosphate (ADP) Receptor Antagonists The Case for Adding Thienopyridines to Aspirin. Currently, platelet inhibitory treatment with a combination of aspirin (acetylsalicylic acid) and P2Y12 receptor inhibition with the thienopyridine, clopidogrel is recommended for patients with acute coronary syndrome (ACS) as well as those undergoing percutaneous coronary intervention (PCI) with stent implantation. This dual antiplatelet therapy has received Class I recommendations in current clinical practice guidelines for unstable angina/non-STEMI (UA/NSTEMI), STEMI,

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and PCI.135,136 Thienopyridines are a subcategory of antiplatelet medications that prevent platelet aggregation through the binding of select, extracellular cysteine residues on the P2Y12 receptor located on the platelet membrane. Thienopyridine antiplatelet agents interfere with platelet activation and aggregation induced by ADP. Currently, three members of the thienopyridine class of antiplatelet agents, ticlopidine, clopidogrel and prasugrel, are available for clinical use. All three agents are prodrugs and require conversion to an active metabolite to exhibit an antiplatelet effect (Figure 8). The active metabolite of the thienopyridine binds irreversibly to the P2Y12 receptor, blocking the binding of ADP and thereby inhibiting platelet activation and aggregation. In addition to patients with STEMI thienopyridines have become a universally accepted cornerstone of treatment, particularly before, during, and after percutaneous coronary intervention (PCI), making a significant decrease in the rate of 30-day major adverse cardiac events (MACEs) in studies that initially compared ticlopidine and aspirin with aspirin alone or with warfarin and aspirin (p = 0.0001).137 In time Clopidogrel showed a better tolerance profile than ticlopidine,138 and the added benefit of a loading dose and long-term treatment for clopidogrel was suggested by the CREDO (Clopidogrel for Reduction of Events During Observation) study. 137-139 This was finally validated in a meta-analysis of combined registries and randomized studies.140 Clopidogrel is currently the thienopyridine of choice. The Clopidogrel as Adjunctive Reperfusion Therapy - Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial,141 a double-blind, randomized, placebo-controlled trial, randomized 3,491 STEMI patients treated with standard thrombolytic therapy, aspirin, and heparin to either clopidogrel 300-mg loading dose followed by 75 mg/day for 30 days or to placebo. This study showed that there was a 36% odds reduction in the clopidogrel group compared to placebo for the primary endpoint of infarct- related occlusion of arteries on angiography or death or MI recurrence before angiography which was performed two to eight days after lysis. In addition there was also a significant reduction of 20% in the major cardiovascular events (cardiovascular death, recurrent MI or recurrent ischemia requiring emergent revascularization) within 30 days of presentation. A sub study, PCI –CLARITY142 also revealed that the clopidogrel treatment group was also effective in the reduction of major cardiovascular events in the 1,836 patients who underwent percutaneous coronary intervention (PCI) after fibrinolysis. A more ambitious COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group study143 involved 45,852 patients admitted to 1,250 hospitals within 24 hours of suspected acute MI onset were randomly allocated clopidogrel 75 mg daily (n=22, 961) or matching placebo (n=22, 891) in addition to aspirin 162 mg daily. In the trial 93% of patients had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Patients allocated to the clopidogrel arm produced a highly significant 9% proportional reduction in death, reinfarction, or stroke (2121 [9·2%] clopidogrel vs. 2310 [10·1%] placebo; p=0·002), correspond-

ing to nine fewer events per 1000 patients treated for about two weeks. There was also a significant 7% (1-13) proportional reduction in any death (1,726 [7·5%] vs. 1845 [8·1%]; p=0·03) (Figure 9). These findings of death, reinfarction, and stroke seemed consistent across a wide range of patients and independent of other therapeutic modalities used. There appeared to be no significant excess risk noted with clopidogrel, either overall (134 [0·58%] vs. 125 [0·55%]; p=0·59), or in patients older than 70 years or in those given fibrinolytic therapy. The metoprolol arm of COMMIT144 showed that giving three intravenous doses of 5 mg metoprolol within 24 hours of the onset of a heart attack, followed by 200 mg daily oral doses while in the hospital, significantly reduced risk of reinfarction and ventricular fibrillation by 15–20%, but increased the relative risk of cardiac shock by about 30%. Risk of shock was elevated on the first two days but not subsequently. The overall balance of these different effects was about even, with no clear reduction in hospital mortality for any particular type of patient. Risk of harm with metoprolol was higher in patients ≥70 years of age, rated as Killip class III, or with systolic blood pressure <120 mm Hg or heart rate ≥110 beats/min where the hazards of early intravenous metoprolol appeared to outweigh any benefits.

Thienopyridine Metabolism, Pharmacokinetics and Polymorphic Genetic Variants Despite the efficacy of this dual antiplatelet therapy treatment on both STEMI145 and PCI patients146,147 at least 15–40% of these patients are poor responders to treatment, in terms of ADP-induced platelet aggregation.148-151 As a result such patients are at increased risk of myocardial infarction, stent thrombosis, and death as revealed in several trials.152-155 Active metabolites of the thienopyridine prodrugs (ticlopidine, clopidogrel, and prasugrel) metabolized in the liver and the intestines (Figure 7) to active metabolites that covalently bind to the P2Y12 receptor, causing irreversible platelet inhibition. Although the thienopyridines require cytochrome P450 (CYP450) metabolism for generating active metabolites, the respective pathways differ among the prodrugs. Ticlopidine is metabolized by at least five main pathways resulting in at least 13, mostly inactive, metabolites156,157 of which only one formed through a CYP-dependent pathway, appears to have antiplatelet activity157,158 Clopidogrel is metabolized by two pathways. While one pathway de-esterifies most of the given dose to inactive metabolites,159 the other pathway goes through at least two CYP-dependent steps to convert clopidogrel to its active metabolite.160,161 Of the multiple CYP enzyme isoforms identified so far, the main contributors to active metabolite formation appear to be CYP1A2, CYP3A4/5, and CYP2C19 162-164). Defective genetic variants, CYP2C19 and possibly also CYP2C9 and CYP2B6, appear to be associated with decreased plasma concentrations (AUC and Cmax) of the active metabolite, lower platelet inhibition, and poor-responder status165-167 (http:// eurheartj.oxfordjournals.org/content/30/16/1964.full- ref-32 )

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Genetic polymorphism in several genes involved in CYP450 metabolism and in the expression of platelet receptors have been proposed to explain part of the variability in clopidogrel responsiveness between individuals. The CYP2C19 defective genotypes, like CYPC19*2, appear to be common with frequencies ranging from 20 to 30% in Caucasians, 30 to 45% in African-Americans, but up to 50 to 65% in East Asians 164-166. This translates to ethnic differences in clinical efficacy of clopidogrel in the larger population. In view of the above considerations on March 12, 2010, the US Food and Drug Administration (FDA) added a Boxed Warning (black box) to the label for clopidogrel (Plavix) regarding patients who do not effectively metabolize the drug and therefore may not receive the full benefits of the drug. Moreover, many physicians refrain from administering clopidogrel prior to obtaining coronary angiography, since this irreversible platelet inhibitor has been associated with an increased risk of perioperative bleeding should coronary-artery bypass grafting (CABG) be required rather than PCI. The TRITON-TIMI 38 (Trials to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) trial in acute coronary syndrome (ACS) patients scheduled for percutaneous coronary intervention (PCI) trial171 randomized 13,608 patients with acute coronary syndromes (with or without ST-segment elevation) who were scheduled for PCI and receiving aspirin were randomly assigned to receive either prasugrel or clopidogrel. Patients received prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for six to 15 months. The study found a significant decrease in the primary end point; the rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke with prasugrel (12.1% for clopidogrel vs. 9.9% for prasugrel, P<0.001). In addition, there was a significant decrease with prasugrel in the rate of myocardial infarction followed by death from cardiovascular causes, including arrhythmia, congestive heart failure, shock, and sudden or unwitnessed death (0.7% vs. 0.4%, P=0.02). Stent thrombosis, a complication of great recent concern, was reduced by approximately 50% in the prasugrel group as compared with the clopidogrel group (2.4% vs. 1.1%; P<0.001), not only for drug-eluting stents but also for bare-metal stents. However, in TIMI, there was a concerning excess major bleeding not related to coronary-artery bypass grafting that was life-threatening in the prasugrel group (1.4%, vs. 0.9% in the clopidogrel group; P=0.01), even fatally so (0.4% vs. 0.1%, P=0.002). For every 1000 patients treated with prasugrel as compared with clopidogrel, 23 MIs were prevented, but at a cost of an excess of six non-CABG-related TIMI major hemorrhages. Thus, clopidogrel’s delayed onset and variability in platelet inhibition appears to be associated with an increased risk of ischemic events and stent thrombosis in poorly responsive patients. Unlike clopidogrel metabolism, prasugrel, a novel third-generation thienopyridine P2Y12 receptor antagonist, first undergoes rapid de-esterification to an intermediate thiolactone, which is then converted to the active metabolite in a single CYP-dependent step.171-174 In addition, the metabolism

of prasugrel is not impacted by reduced function CYP polymorphisms175,176 Therefore, in PCI-treated ACS patients, prasugrel seems to provide a better protection against thrombotic events but with a raised risk of major bleeding. Prasugrel’s apparent higher efficacy is related to its simpler metabolism, more rapid conversion to the active metabolite, and the lack of influence of genetic variability. Prasugrel possesses more rapid, potent, and consistent platelet inhibition than clopidogrel. On July 10, 2009, the US Food and Drug Administration (FDA) approved the use of prasugrel in patients with ACS who are to be managed with PCI. However, much controversy surrounded the approval of prasugrel. There is still some uncertainty about the role this drug will play in the prevention of myocardial infarction, as well as its optimal dosing and adverse effects profile. It is possible that Prasugrel may be the preferred therapy in patients with diabetes mellitus. Prasugrel should not be used in patients with previous stroke, transient ischemic attack, or other intracranial pathology and is not recommended in patients 75 years or older, or in patients weighing less than 60 kg. The 2009 joint American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) STEMI/PCI focused update guidelines recommend administration of either clopidogrel (300 to 600 mg loading dose) as early as possible prior to, or at the time of, primary or non-primary PCI or prasugrel (60 mg loading dose) as soon as possible for primary PCI in STEMI patients undergoing planned PCI.

Direct-Acting P2Y12 Inhibitors

As discussed above, thienopyridines (ticlopidine, clopidogrel, and prasugrel) are indirectly acting platelet inhibitors where the active metabolites of the thienopyridine prodrugs covalently and irreversibly bind to the P2Y12 receptor during the entire lifespan of the platelet (See Table 2). Thus the delayed onset of action of these drugs is a disadvantage especially during PCI. Moreover, their irreversible antiplatelet effect represents a major disadvantage for patients who do not undergo PCI but are in need of urgent CABG. Because of this reason, many centers defer the administration of thienopyridines in patients with STEMI until angiography confirms the need for PCI. However newer, direct-acting P2Y12 inhibitors like cangrelor and ticagrelor change the conformation of the P2Y12 receptor resulting in reversible inhibition of the receptor. Ticagrelor (Brilinta, AstraZeneca) is the first in a new chemical class, the CPTPs (cyclopentyl-triazolo-pyrimidines) and is chemically distinct from the thienopyridines, such as clopidogrel and prasugrel. It is administered orally and has a reversible P2Y(12) receptor inhibitory effect and is chemically distinct from the thienopyridines, such as clopidogrel and prasugrel, but has a more rapid onset and with a more pronounced platelet inhibition that is nearly double that of clopidogrel.177 In the PLATelet Inhibition and Patient Outcomes (PLATO) trial (178), 18,624 patients admitted to the hospital with ACS recruited from 862 sites in 43 countries between 2006 and 2008 and with or without ST-segment elevation were randomized to

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receive either ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter) in a double-blind, double-dummy fashion for one year. Patients left the study at their six- or nine-month visit if the targeted number of 1,780 primary end points had occurred by that time. Patients also received aspirin, at a dose of 75 mg to 100 mg day, unless they could not tolerate the drug. At 12 months, the primary end point, a composite of death from vascular causes, MI, or stroke, had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those taking clopidogrel (p<0.001). Overall mortality was reduced from 6% to 4.9%. Definite stent thrombosis was reduced from 2.6% in the clopidogrel group to 1.6% in the ticagrelor group. Major bleeding occurred in 9.3% of clopidogrel patients versus 9.0% of ticagrelor patients. In the PLATO study, a subset of 8,430 patients who were in the midst of STEMI and were scheduled for primary percutaneous coronary intervention (PCI) with stenting received the investigational drug ticagrelor or clopidogrel in addition to aspirin.179 Out of this clinical subset, 4,201 STEMI patients were allocated to ticagrelor 180 mg loading dose followed by 90 mg twice daily plus aspirin, and 4,229 to clopidogrel 300 mg loading dose (with provision for an extra 300 mg clopidogrel at PCI) followed by 75 mg daily for six to twelve months, plus aspirin. The sub-analysis revealed that the clopidogrel treatment arm compared to ticagrelor resulted in a reduction of cardiovascular events (composite of CV death, heart attack and stroke) for up to a year (ticagrelor vs. clopidogrel, 9.3% vs. 11.0%, P=0.02). There was a statistically significant reduction in myocardial infarction (4.7% vs. 6.1%, P=0.01). In addition no increase in major bleeding (9.0% vs. 9.3%, P=0.63) was observed. For these STEMI patients, the benefit observed with ticagrelor appeared to increase over time. However, new side effects, particular to the use of ticagrelor but previously not seen with either clopidogrel or prasugrel, were more evident. These included dyspnea, bradyarrhythmia, and increased serum levels of uric acid and creatinine. As in the main trial, ticagrelor was associated with a significantly higher rate of dyspnea than was clopidogrel (12.9% vs. 8.3%, respectively; p<0.0001). On July 28, 2010, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to recommend

approval of antiplatelet drug ticagrelor in the management of STEMI and also unstable angina and NSTEMI. Cangrelor is an adenosine triphosphate (ATP) analog which reversibly and directly, without any biotransformation, inhibits the P2Y12 receptor.180,181 This apparent dream drug in some respects is characterized by a) rapid onset of action, reaching steady-state concentrations within minutes; b) great degree of platelet inhibition (>90%); c) dose-dependent effects; and d) rapid onset of action, since it has an extremely short half-life (two to five minutes) due to rapid deactivation by plasma ectonucleotidases, with the platelet response approaching baseline within 60 minutes after discontinuation of the drug infusion and also appeared well tolerated during a prolonged infusion of up to 72 hours.182,183 It is the first such drug to be administered intravenously. Harrington et al.184 and Bhatt et al.185 reported on the results of the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PCI trial and the CHAMPION PLATFORM trial respectively. Unfortunately, both CHAMPION trials had negative results and insufficient evidence for clinical effectiveness for cangrelor but questions about the flawed design and reporting of both these trials have been raised.186 Although Cangrelor underwent these two phase-3 trials, which were stopped early for lack of efficacy, nevertheless, it is still being studied as a potential bridge for patients on clopidogrel who need to go off the drug to undergo surgery. There is a current ongoing study, BRIDGE (maintenance of platelet inihiBition with cangRelor after discontinuation of thienopyriDines in patients undergoing surgery) trial (NCT 00767507) to test this hypothesis. Elinogrel (PRT060128), a quinazorinedione, is a reversible, potent and competitive inhibitor of the P2Y12 receptor that can be administered by both oral and intravenous routes and rapidly achieves near complete platelet inhibition. At present Elinogrel is in the preliminary stages of development, with phase I studies showing some promising pharmacologic properties that include: a) rapid onset of action (almost immediate if administered intravenously); b) higher degree of platelet inhibition than clopidogrel; and c) rapid onset of action, with a half-life of 50 minutes and 12 hours for intravenously and oral administration, respectively.187 In poor clopidogrel responders a single oral dose of elinogrel improved platelet inhibition in stable

Table 2: Platelet P2Y12 inhibitors.

Clopidogrel

Prasugrel

Ticagrelor

Elinogrel

Thienopyridine

Thienopyridine ATP analog

Cyclopentyltriazolopyridine

Quinazolinedione

Development Status Approved in 1997

Approved in 2009

Phase III completed in 2009

Phase II ongoing

Administration

Oral

Parenteral

Oral

Oral and parenteral

Bioavailability

Prodrug

Direct-acting

Receptor inhibition

Irreversible

Reversible

Frequency

Daily

Bolus and infusion

Twice daily

Group

ATP indicated adenosine triphosphate

Cangrelor

Modified after Angiollio and Ferreiro. Rev Esp Cardiol. 2010; 63:60-76.

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patients with coronary artery disease.188 In the ERASE-MI trial (Early Rapid ReversAl of Platelet ThromboSis with Intravenous PRT060128 Before PCI to Optimize REperfusion in Acute MI), the initial phase 2 results, evaluating the safety and efficacy of intravenous elinogrel in patients with STEMI prior to primary PCI, showed that the incidence of bleeding events was infrequent and that no differences were demonstrated between elinogrel and placebo in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count, or ST resolution.188 Currently, the ongoing INNOVATE (a Randomized, Double-Blind, Active-Controlled Trial to Evaluate Intravenous and Oral PRT060128, a Selective and Reversible P2Y12 Inhibitor, vs. Clopidogrel, as a Novel Antiplatelet Therapy in Patients Undergoing Non-Urgent PCI) trial (NCT00751231) is evaluating clinical efficacy, biological activity, tolerability and safety of PRT060128 in patients undergoing non-urgent PCI, testing three doses of elinogrel (oral 50, 100, and 150 mg) twice daily, following an intravenous bolus.189

Anticoagulant Therapy The American College of Cardiology, the American Heart Association, and the European Society of Cardiology recommend the use of intravenous unfractionated heparin, with the dose adjusted for the activated clotting time, during percutaneous coronary intervention (PCI).189,190 On the basis of expert consensus, unfractionated heparin is recommended in patients undergoing primary PCI (class I =treatment should be administered). Unfractionated Heparins (UFH) are glycosaminoglycans (GAGS) consisting of chains of alternating residues of D-glucosamine and a uronic acid, either gluconic acid or iduronic acid. Heparin in particular is a heterogeneous polydispersed mixture of sulfated polysaccharides with a molecular weight range of 3000 to 30 000 Da (mean, 15 000 Da), whose anticoagu1ant activity is accounted for by a unique pentasaccharide with a high affinity binding sequence to antithrombin 111 (ATIII). Heparin produces its major anticoagulant effect by inactivating thrombin and activated factor X (factor Xa) through an antithrombin (AT)-dependent mechanism. Heparin binds to AT through the high-affinity pentasaccharide, which is present on about a third of heparin molecules. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and AT, whereas binding to the enzyme is not required for inhibition of factor Xa. Molecules of heparin with fewer than 18 saccharides lack the chain length to bridge between thrombin and AT and, therefore, are unable to inhibit thrombin. In contrast, very small heparin fragments containing the pentasaccharide sequence inhibit factor Xa via AT. By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of platelets and of factors V and VIII. Historically, unfractionated heparin (UFH) has been widely used as an anti-coagulant in the treatment of STEMI for greater than 50 years. The benefits of UFH combined with fibrinolytic therapy have been established. Adding UFH to fibrinolysis with streptokinase (SK) has been shown to reduce death and re-

infarction,192 while combining UFH with fibrin-specific agents is thought to help achieve and maintain coronary arterial patency.193,194 However disadvantages to the use of UFH include its sometimes difficult-to-manage effects on coagulation because of its narrow therapeutic window, necessitating the need for continuous monitoring of coagulation, the potential for inducing platelet activation, and the risk of Heparin Induced Thrombocytopenia/Heparin Induced Thrombosis-Thrombocytopenia Syndrome (HIT/HITTS). UFH can be fragmented and depolymerized to Low-molecular-weight heparins (LMWHs), by nitrous acid depolymerization (fraxiparin and fragmin), benzylation followed by alkaline depolymerization (enoxaparin=lovenox), or by enzymatic (heparinase) depolymerization (logiparin), LMWHs consisting of only short chains of polysaccharides having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. The resulting LMWHs contain the unique pentasaccharide required for specific binding to ATIII, but in a lower proportion than is contained in their parent UFH. Physiologically and clinically Low-molecular-weight heparins possess some pharmacological and pharmacokinetic advantages over unfractionated heparin. They have a predictable pharmacokinetic profile, high bioavailability, and long plasma half-life, all of which result in effective levels of anticoagulant activity after subcutaneous administration without need of constant laboratory monitoring.195,196 Low-molecular-weight heparins, such as enoxaparin, are therefore an attractive potential replacement for UFH because of the convenient subcutaneous route of administration and reliable anticoagulation effects, eliminating the need for therapeutic monitoring. Five different LMWHs (Enoxaparin, Fragmin, Fraxiparin, Logiparin, and Lomoparin) have been approved for clinical use in Europe and three LMWHs (Enoxaparin, Logiparin, and RD heparin) and the heparinoid Lomoparin have been evaluated in largescale randomized trials in North America. The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial demonstrated that enoxaparin as adjunctive anticoagulant therapy for the duration of the index hospitalization was superior to the standard two-day UFH regimen in patients with STEMI treated with fibrinolytic therapy.197 In the ExTRACT-TIMI 25 trial, alteplase, tenecteplase, reteplase, or SK was administered to STEMI patients at the discretion of the treating physician, and 30-day outcomes were evaluated. In a pre-specified subgroup analysis of this study of patients with STEMI undergoing pharmacological re-perfusion, recurrent MI, and ischemic events leading to urgent revascularization were significantly reduced (12.0% vs. 9.9%, p < 0.001); with the enoxaparin strategy compared with UFH as adjunctive anticoagulant therapy in conjunction with fibrin-specific lytics. However, more major bleedings were observed in the enoxaparin group (1.4 vs. 2.1%, p < 0.001).198

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Thrombin Inhibitors Fondaparinux, a synthetic pentasaccharide, is the first of the selective Xa inhibitors with clinical importance. It is an indirect factor Xa inhibitor. It is a pentasaccharide designed specifically to bind to plasma antithrombin. This binding induces a conformational change in antithrombin which increases the affinity of antithrombin for factor Xa, potentiating the natural inhibitory effect of antithrombin against factor Xa. The Fifth Organization to Access Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial demonstrated that fondaparinux is an efficient and safe anticoagulant in the treatment of acute coronary syndromes without ST elevations.199 The OASIS-6 trial200 showed a reduction in mortality and reinfarctions by fondaparinux compared with unfractionated heparin in more than 10,000 patients with STEMI. Treatment of STEMI patients with fondaparinux was safe and not associated with an increase in bleedings or hemorrhagic strokes. The data of the OASIS-6 trial suggest that selective factor Xa inhibition with fondaparinux is an attractive new antithrombotic strategy in the treatment of STEMI. Fondaparinux is easy to use. A single daily subcutaneous administration of 2.5 mg can provide a stable and predictable anti-coagulation without the need for laboratory control of coagulation parameters. Besides, it is not associated with the risk of heparin-associated thrombocytopenia. As a result it can be used in a wide range of settings for various patients. However, for primary PCI in STEMI patients, the actual data of the OASIS-6 trial suggested that at least during the intervention, unfractionated heparin is necessary in addition to fondaparinux to avoid catheter thrombosis and ischemic complications.

whom percutaneous coronary intervention is done. Moreover, anticoagulation with bivalirudin alone suppresses adverse ischemic events to a similar extent as does heparin plus glycoprotein IIb/IIIa inhibitors, while significantly lowering the risk of major hemorrhagic complications.205 For STEMI patients undergoing PCI there may soon be a transition from UFH or LMWH towards bivalirudin with or without GP IIb/IIIa inhibitor in the cardiac catheterization lab.

Glycoprotein IIb/IIIa Receptor Inhibitors Integrins are cell surface receptors that transduce information between the cell and its extracellular matrix. They are obligate heterodimers with two distinct chains, called the α (alpha) and β (beta) subunits. Glycoprotein IIb/IIIa (gpIIb/IIIa, also known as integrin αIIbβ3), is an integrin complex acting as a fibrinogen receptor on the platelet cell surface. It is the most abundant platelet membrane glycoprotein found in humans and is also involved in platelet activation as a key mediator of thrombus formation. The sine qua non of platelet activation is the conformational changes of the GP IIb/IIIa receptor—with subsequent transformation from a low- into a high-affinity state—allowing for binding of fibrinogen and vWF.206 Inhibiting this process of platelet activation has been a recognized therapeutic modality in the past decade in ACS and particularly during percutaneous coronary interventions (PCI).

Bivalirudin (Angiomax or Angiox) is a synthetic congener of the naturally occurring drug hirudin (found in the saliva of the medicinal leech Hirudo medicinalis). It is a specific and reversible direct thrombin inhibitor (DTI). It does not have the many limitations seen with indirect thrombin inhibitors, such as heparin. Bivalirudin is a short, synthetic peptide that is potent, highly specific, and a reversible inhibitor of thrombin,201,202 inhibiting both circulating and clot-bound thrombin,203 as well as inhibiting thrombin-mediated platelet activation and aggregation.202 Thrombin is a serine proteinase that plays a central role in the thrombotic process. It cleaves fibrinogen into fibrin monomers, activates Factor V, VIII, and XIII, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus. Thrombin also promotes further thrombin generation and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.

The glycoprotein IIb/IIIa receptor inhibitors, abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat), have all been approved by the FDA for use in ACS. They all have similar mechanisms of action to inhibit platelet aggregation. Abciximab is a large fragment of a mouse–human chimeric monoclonal antibody that interferes with platelet aggregation by steric hindrance. These huge molecules basically wrap around each platelet, thus preventing glycoprotein IIb/IIIa receptor binding but also the binding to other receptors responsible for platelet adhesion. However, by preventing both platelet adhesion and aggregation, abciximab may result in more bleeding complications than more specific GP IIb/IIIa inhibitors. On the other hand Tirofiban and eptifibatide are relatively small, synthetic molecules with high affinity for glycoprotein IIb/IIIa binding only and compete with fibrinogen for the glycoprotein IIb/IIIa receptor in a concentration-dependent fashion and thereby preventing platelet aggregation. Tirofiban and eptifibatide apparently are non-immunogenic and, therefore, suitable for repeat infusions. They also have a shorter half life (90-120 minutes) compared to abciximab (12 hours). Since they are mainly renally cleared, their doses should be adjusted in patients with renal impairment. To maximize clinical benefits all three drugs should at least achieve 80% inhibition of platelet aggregation.

A subgroup analysis of 7,789 patients from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial204 demonstrated that substitution of unfractionated heparin or enoxaparin with bivalirudin results in comparable clinical outcomes in patients with moderate and high-risk acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors and in

GP IIb/IIIa blockers were launched in the 1990s with great fanfare on the assumption that the inhibition of the ‘final common pathway’ of platelet aggregation would translate into an improvement in prognosis of patients undergoing PCI or presenting with ACS.207 Unfortunately, much of the evidence favoring the use of GP IIb/IIIa inhibitors for STEMI was established in

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the era before dual oral antiplatelet therapy and largely by placebo-controlled comparisons.208-210 The three trials that have evaluated GP IIb/IIIa antagonists as adjuncts to oral antiplatelet therapy in the setting of primary PCI have not established whether GP IIb/IIIa antagonists provide significant additional benefit to STEMI patients who have received dual-antiplatelet therapy before catheterization. In the BRAVE-3 study,211 the composite of death at 30 days, recurrent myocardial infarction (MI), stroke, or urgent revascularization of the infarct-related artery was not significantly different in the two groups (abciximab 5%, placebo 3.8%; P=0.4). A randomized, placebo-controlled, multicenter European trial ON-TIME 2212 found no significant difference in death, recurrent MI, or urgent target-vessel revascularization (TVR) between the tirofiban and placebo groups at 30 days. In the HORIZONS-AMI trial,213 patients undergoing primary PCI for STEMI and who had been given aspirin and a thienopyridine before catheterization were randomized to treatment with UFH plus a GP IIb/IIIa receptor antagonist (abciximab or double-bolus eptifibatide) or to bivalirudin alone with provisional IIb/IIIa. At 30 days, rates of major bleeding and total adverse events were higher among patients treated with GP IIb/IIIa antagonists and heparin than among those given bivalirudin alone. In light of these findings the 2009 STEMI and PCI Focused Updates of the American College of Cardiology Foundation/ American Heart Association (ACCF/AHA) Task Force on Practice Guidelines advises that, in the setting of dual-antiplatelet therapy with UFH or bivalirudin as the anticoagulant, current evidence indicates that adjunctive use of a GP IIb/IIIa antagonist can be useful at the time of primary PCI but cannot be recommended as routine therapy.214

Percutaneous Coronary Intervention for Myocardial Revascularization In 1929, Werner Forssmann, a young surgical resident from Eberswald, Germany, was tooling around in an attempt to find a safe and effective way to inject drugs for cardiac resuscitation. He anesthetized his left elbow, inserted a catheter into his antecubital vein, and confirmed the position of the catheter tip in the right atrium by use of radiography, thus performing the first documented human cardiac catheterization.215 Forssmann further elaborated on his experiments to include intracardiac injection of contrast material through a catheter placed in the right atrium. By 1958, Mason Sones had performed selective coronary arteriography in a series of more than 1,000 patients.216 Melvin Judkins, a radiologist who had studied coronary angiography with Sones, introduced a series of specialized catheters and created his own system of coronary imaging in 1967 and perfected the transfemoral approach.217 These contributions coupled with the development of nontoxic contrast media paved the way for the development of coronary angiography. Back in 1964, Charles Dotter and Melvin Judkins had described a new technique for relieving stenosis of the iliofemoral arter-

ies with rigid dilators.218 Although this technique had been developed in Oregon, the procedure was largely ignored in the United States because of technical difficulties and complications but was widely adopted to treat large numbers of patients in Europe. Meanwhile in 1974 Andreas Gruentzig in Zurich substituted a balloon-tipped catheter for the rigid dilator and inaugurated the first peripheral balloon angioplasty in a human.219 After perfecting coronary angioplasty in animals, Gruentzig then went on to perform intraoperative balloon angioplasty on the human heart for the first time.220 Soon thereafter, Gruentzig and his colleagues described their technique of percutaneous transluminal coronary angioplasty (PTCA) as used in a series of 50 patients.221 This Gruentzig technique was widely adopted and universally applied. The era of percutaneous coronary intervention had arrived. This technique quickly evolved into applications such as coronary atherectomy (1986) and coronary stenting (1987) and by 1997, angioplasty had become one of the most common medical interventions in the world. In 1986 results from a small, randomized trial involving 56 patients suggested that percutaneous coronary intervention (PCI) could be superior to intracoronary streptokinase therapy in improving left ventricular function.222 A systematic review of ten small trials involving a total of 2,606 patients and published in 1997 223 compared either streptokinase or tissue-type plasminogen activator with primary PCI. This revealed a statistically significant 34% reduction in mortality for PCI (6.5% v. 4.4%; p = 0.02), a 47% reduction in nonfatal reinfarction (5.3% v. 2.9%; p = 0.04), and a substantial reduction in hemorrhagic stroke (1.1% v. 0.1%; p < 0.001) at 30 days.216 PCI, therefore, saved 21 more lives per 1000 patients compared with thrombolytic therapy (and 40 to 50 lives saved with PCI compared with no therapy). In addition PCI avoids increased rates of reinfarction and intracranial bleeds, two of the most serious complications of thrombolytic therapy. Multiple registries and randomized clinical trials have now solidly confirmed the benefits of PCI over thrombolysis.224-228 The Danish Trial in Acute Myocardial Infarction-2 (DANAMI-2) trial enrolled 1,572 patients and randomized patients arriving at an invasive hospital within 12 hours of ST-segment elevation MI (STEMI) to fibrinolysis with tPA or primary PCI. In addition, patients who were admitted to noninvasive hospitals were randomized to immediate treatment with thrombolytic therapy in the local hospital or acute ambulance transfer for primary angioplasty.229 Compared to fibrinolysis with front-loaded tPA, primary PCI in patients with STEMI reduced the combined incidence of death, recurrent MI, or stroke from 14% to 8% (relative risk reduction [RRR], 43%; p =0.0003). In transfer sites, the rate of combined end point was 14% in those treated with thrombolysis compared to 9% in those treated with PCI (RRR, 40%; p =0.003). In nontransfer sites, the combined end point was 12% in the thrombolytic group and 7% in the primary PCI group (RRR, 45%; p =0.048). Again back in 1964, well before the introduction of coronary angioplasty by Grüntzig, Dotter and Judkins had proposed the use of percutaneously introduced prosthetic devices to maintain the luminal integrity of atheromatous vessels.218 However, it was Palmaz et al.230 who in 1985 introduced the use of balloon-

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mounted stents in peripheral arteries. Schatz et al. subsequently modified the Palmaz stent, which led to the development of the first commercially successful stent, the Palmaz–Schatz stent.231 However, it was Puel and Sigwart232 who were the first to implant a self-expanding mesh device in humans in March 1986. The following year Sigwart and colleagues described the use of this particular stent for emergency vessel closure during balloon angioplasty.233 The reasoning was that the device would act as a scaffold shunting intimal and medial flaps away from the lumen, thus maintaining radial support to offset vascular elastic recoil to obviate restenosis.234 The most serious complication of PCI results when there is an abrupt closure of the dilated coronary artery within the first few hours after the procedure. Abrupt coronary artery closure occurs in 5% of patients after simple balloon angioplasty and is responsible for most of the serious complications related to percutaneous coronary intervention. Abrupt closure is due to a combination of tearing (dissection) of the inner lining of the artery, blood clotting (thrombosis) at the balloon site, and constriction (spasm) or elastic recoil of the artery at the balloon site. Two important randomized clinical trials in 1993 compared the Palmaz–Schatz stent with balloon angioplasty. The Netherlands Stent (BENESTENT) study235 and the North American Stent Restenosis Study (STRESS) 236 separately demonstrated that intracoronary stents significantly reduced the incidence of angiographic restenosis (defined as more than 50% narrowing of a previously stented site, as measured by quantitative coronary angiography) and repeated angioplasty in patients with discrete, new lesions in large target vessels. This firmly established the elective placement of coronary stents as a standard treatment for myocardial revascularization. By 1999, stenting constituted 84.2% of percutaneous coronary interventions. Currently, mortality rates for PCI from experienced operators in large series range from 0.5 to 1.7 percent. 237-242 Overall, the improvements in devices, the use of stents, and aggressive antiplatelet therapy have significantly reduced the incidence of major periprocedural complications of PCI in the last 20 to 25 years. This is evidenced by the fact that, the need for emergent coronary bypass surgery (CABG) decreased in two series from 1.5% in 1992 to 0.14% in 2000,243 and from 2.9% in 1979 to 1994 to 0.3% in 2000 to 2003.244 Therefore, with respect to parameters utilized for assessment of success in primary PCI, which include TIMI flow, myocardial blush grades, and ST-segment resolution mechanical revascularization, (PCI) appears to perform better than lytic therapy. Primary percutaneous coronary intervention (PCI) to restore coronary blood flow is the current standard of care for ST-elevation myocardial infarction (STEMI) PCI. It carries a class IA recommendation from the American College of Cardiology (ACC)/American Heart Association (AHA) and 2005 Society for Cardiovascular Angiography and Interventions (SCAI) PCI guidelines. In addition the Centers for Medicare & Medicaid Services (CMS)/The Joint Commission have established a door-to-balloon time of less than 90 minutes as one of the core clinical performance measures.

Multiple “atherectomy” devices were also initially developed as adjuncts to percutaneous coronary intervention, including the excimer laser for photoablation of plaque, the use of a high-speed diamond-encrusted drill for rotational atherectomy for mechanical ablation of plaque, and directional atherectomy device for cutting and removal of plaque. These devices were initially thought to decrease the incidence of restenosis but in clinical trials were shown to be of little additional benefit and are now only used in selective cases as adjuncts to standard percutaneous coronary intervention. It is self-evident that stent implantation would be inherently thrombogenic, initiating a complex interaction between the metal surface and blood components, resulting in activation of platelets, the complement system, and protein deposition. Indeed, this results in the deposition of thrombi over the surface of the stent (http://www.nejm.org/doi/full/10.1056/NEJMra051091 - ref15) and the establishment of a confluent endothelial monolayer,245 a process leading to restenosis.

Drug-Eluting Stents (DES) Drug-eluting stents are metal stents that have been coated with a polymer containing an antiproliferative agent, gradually released over time after the stent is inserted. Theoretically, this should provide sustained inhibition of the neointimal proliferation (the process that is responsible for restenosis) occurring as a result of vascular injury. The so-called first-generation drug-eluting stents released sirolimus, rapamycin, a natural cytostatic macrocyclic lactone with potent antiproliferative, anti-inflammatory, and immunosuppressive effects, acting by inhibiting the activation of the mammalian target of rapamycin (mTOR), ultimately causing arrest of the cell cycle, or paclitaxel, a chemotherapeutic agent that suppresses assembly and stabilization of microtubule. The Randomized Study utilizing the Sirolimus-eluting Bx Velocity Balloon Expandable Stent (RAVEL) demonstrated a stupendous 0% rate of restenosis, as measured by angiography, and complete inhibition of neointimal hyperplasia in the group that received a sirolimus-eluting stent. While 23% of the control group at one year required percutaneous revascularization of the treated lesion, the study group that received a sirolimuseluting stent group required 0% revascularization. This study led to the approval of the device in Europe.246 The randomized, double-blind Sirolimus Eluting Stent in de Novo Coronary Lesions (SIRIUS) trial, involving 1,055 patients, similarly had favorable results that were used to gain approval of the device by the Food and Drug Administration (FDA) in the United States in 2003.247 The SIRIUS trial confirmed the safety and efficacy of the sirolimus-eluting stent in single, previously untreated coronary artery lesions, with a lower rate of in-stent restenosis than found with otherwise identical bare-metal stents (3.2% vs. 35.4%, P<0.001). More studies confirmed that DES appeared to be superior to bare-metal stents (BMS) and to balloon angioplasty in reducing the magnitude of neointimal proliferation, the incidence of clinical restenosis, and the need for vascular reintervention.248,249

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Bridled with new found enthusiasm for DES, physicians extended the use of drug-eluting stents to patients with clinical and anatomical features beyond those of patients in the FDAapproval trials. The use of drug-eluting stents in this context is called “off-label.” In order to address this concern, in December 7-8, 2006, the FDA convened a public meeting of the Circulatory System Devices Advisory Committee to specifically: (1) provide a forum for the presentation of clinical data relevant to the issue of DES thrombosis, both when DES are used according to their label and when they are used off-label in more complex cases beyond their FDA approved uses; and (2) address the appropriate duration of the use of clopidogrel with DES patients. The FDA panel observed that at least 60% of current DES use is off-label, and off-label use is associated with increased events. However, the panel acknowledged that “with more complex patients there is an expected increased risk in adverse events” and also noted that the FDA does “not regulate how [DES] are used by individual clinicians in the practice of medicine.”250

Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The author has stated that no such relationships exist.

Late stent thrombosis (i.e., thrombosis occurring 30 days or more after stent implantation) is more likely to occur with drug-eluting stents than with bare-metal stents.251 As a result of continued gradual release of the antiproliferative agent, endothelialization of the stent struts is effectively inhibited. This then allows the struts to continue serving as a focus for platelet aggregation and thrombus formation. Indeed, there is angioscopic evidence that three to six months after stent deployment bare-metal stents were completely endothelialized, whereas 87% of drug-eluting stents were not, and thrombi were present in 50% of the drug-eluting stents.252 While the risk of late stent thrombosis with drug-eluting stents is relatively small (0.5 to 3.1%), it does not diminish with time and its occurrence is unpredictable, often catastrophic, with fatal myocardial infarction occurring in up to 65% of such patients.253 Second-generation drug eluting stents differ from the firstgeneration stents in the shape of the stent frame and the nature of the polymer layer, a reservoir which delivers the antiproliferative agent.254 In the second-generation drug-eluting stents, a semi-synthetic sirolitmus analogue, everolimus, is released from a cobalt-chromium stent frame with thin struts coated by a biocompatible fluoropolymer. In contrast, paclitaxel is released from a polymer coating affixed to less flexible thicker stainless steel struts in the older drug-eluting stents. Stone et al. recently showed that a second-generation everolimus-eluting stent is superior to a first-generation paclitaxel-eluting stent in preventing the clinical manifestations of stent thrombosis and restenosis.255 However, it is not yet clear which of these two differences is responsible for the improved outcomes with the second-generation stents. Perhaps these newer stents have improved efficacy or delivery of the antiproliferative drug (everolimus) resulting in less neointimal proliferation and restenosis. Leslie Mukau, MD, FAAEP, FACEP, is Chairman, Department of Emergency Medicine, El Centro Regional Medical Center, El Centro, California.

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controlled trial. Lancet. 2005;366:1622-32. 145. COMMIT Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebocontrolled trial. Lancet. 2005;366:1607–21. 146. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502. 147. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527-533. 148. Steinhubl SR, Berger PB, Mann JT III, Fry ET, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc. 2002;288:2411-2420. 149. Storey RF, Husted S, Harrington RA, Heptinstall S, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007;50:1852-1856. 150. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038-1047. 151. Wiviott SD, Trenk D, Frelinger AL, O’Donoghue M, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116:2923-2932. 152. Wallentin L, Varenhorst C, James S, Erlinge D, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21-30. 153. Bonello L, Paganelli F, Arpin-Bornet M, Auquier P, et al. Vasodilatorstimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007;5:1630-1636.

vivo metabolism of antiplatelet agent clopidogrel: cytochrome P450 isoforms responsible for two oxidation steps involved in active metabolite formation. Drug Dev Rev. 2005;37(Suppl. 2):99. 163. Kurihara A, Hagihara K, Kazui M, Ishizuka T, Farid NA, Ikeda T. In vivo metabolism of antiplatelet agent clopidogrel: cytochrome P450 isoforms responsible for two oxidation steps involved in active metabolite formation. Drug Dev Rev. 2005;37(Suppl. 2):99. 164. Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos. 2003;31:53-59. 165. Farid NA, Payne CD, Small DS, Winters KJ, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81:735-741. 166. Mega JL, Close SL, Wiviott SD, Shen L, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362. 167. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5:2429-2436. 168. Varenhorst C, James S, Erlinge D, Brandt JT, et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J. 2009;30:1744-1752. 169. Dandara C, Masimirembwa CM, Magimba A, Sayi J, et al. Genetic polymorphism of CYP2D6 and CYP2C19 in east- and southern African populations including psychiatric patients. Eur J Clin Pharmacol. 2001;57:11-17. 170. Myrand SP, Sekiguchi K, Man MZ, Lin X, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008;84:347-361. 171. Yamada H, Dahl ML, Lannfelt L, et al. CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol. 1998;54:479-481. 172. Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:20012015.

154. Buonamici P, Marcucci R, Migliorini A, Gensini GF, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol. 2007;49:2312-2317.

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175. Williams ET, Jones KO, Ponsler GD, Lowery SM, et al. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos. 2008;36:12271232. 176. Farid NA, Payne CD, Small DS, Winters KJ, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81:735-741. 177. Brandt JT, Close SL, Iturria SJ, Payne CD, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5:2429-2436. 178. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with nonST-segment elevation acute coronary syndrome: Primary results of the DISPERSE-2 Trial. J Am Coll Cardiol. 2007; 50:1844-1851. 179. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:10451057.

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180. Steg G et al. Comparison of Ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: results from the PLATelet inhibition and patient Outcomes (PLATO) trial. Presentation at AHA 2009. Final Program Number LBCT.01. 181. Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am Heart J. 2008;156 Suppl:S10-5.

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217. Sones FM Jr, Shirey EK. Cine coronary arteriography. Mod Concepts. Cardiovasc Dis. 1962;31:735–8.

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239. Fischman, DL, Leon, MB, Baim, DS, et al. A randomized comparison of coronary–stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994; 331:496.

221. Hurst JW. The first coronary angioplasty as described by Andreas Gruentzig. Am J Cardiol. 1986;57:185–6.

240. Serruys, PW, de Jaegere, P, Kiemeneij, F, et al. A comparison of balloon– expandable–stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994; 331:489.

222. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med. 1979;301:61–8. 223. O’Neill W, Timmis GC, Bourdillon PD, Lai P, Ganghadarhan V, Walton J Jr, et al. A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med. 1986;314:812-8. 224. Weaver WD, Simes RJ, Betriu A, Grines CL, Zijlstra F, Garcia E, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction. JAMA. 1997;278:2093-8. 225. Magid DJ, Calonge BN, Rumsfeld JS, Canto JG, Frederick PD, Every NR, et al. Relation between hospital primary angioplasty volume and mortality for patients with acute MI treated with primary angioplasty vs thrombolytic therapy. JAMA. 2000;284:3131-8. 226. Widimsky P, Groch L, Zelizko M, Aschermann M, Bednar F, Suryapranata H. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE Study. Eur Heart J. 2000;21:823-31. 227. Grines CL, Westerhausen DR, Grines LL, Hanlon JT, Logemann TL, Niemela M, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction. J Am Coll Cardiol. 2002;39:1713. 228. http://www.cmaj.ca/cgi/ijlink?linkType=ABST&journalCode=jacc&res id=39/11/1713. 229. Widimsky P, Budesinsky T, Vorac D, Groch L, Zelizko M, Aschermann M, et al; PRAGUE Study Group Investigators. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial — PRAGUE-2. Eur Heart J. 2003;24(1):94-104. 230. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13-20. 231. Williams ES, Miller JM. Results from late-breaking clinical trial sessions at the American College of Cardiology 51st Annual Scientific Session. J Am Coll Cardiol. 2002;40(1):1-18. 232. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med. 1979;301:61-68. 233. Palmaz JC, Sibbitt RR, Reuter SR, Tio FO, Rice WJ. Expandable intraluminal graft: a preliminary study: work in progress. Radiology. 1985;156:73-77. 234. Schatz RA, Palmaz JC, Tio FO, Garcia F, Garcia O, Reuter SR. Balloon-expandable intracoronary stents in the adult dog. Circulation. 1987;76:450-457. 235. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med. 1987;316:701-706. 236. de Feyter PJ, de Jaegere PP, Serruys PW. Incidence, predictors, and

241. Topol EJ, Leya F, Pinkerton CA, et al for the CAVEAT study group. A comparison of directional coronary atherectomy versus standard balloon angioplasty. N Engl J Med. 1993;329:221. 242. Maynard C, Chapko MK, Every NR, et al. Coronary angioplasty outcomes in the Healthcare Cost and Utilization Project, 1993-1994. Am J Cardiol. 1998;81:848. 243. Seshadri N, Whitlow PL, Acharya N, et al. Emergency coronary artery bypass surgery in the contemporary percutaneous coronary intervention era. Circulation. 2002;106:2346. 244. Dorros G, Cowley MJ, Simpson J, et al. Percutaneous transluminal coronary angioplasty: Report of complications from the National Heart, Lung, and Blood Institute PTCA registry. Circulation. 1983;67:723. 245. Yang EH, Gumina RJ, Lennon RJ, et al. Emergency coronary artery bypass surgery for percutaneous coronary interventions: Changes in the incidence, clinical characteristics, and indications from 1979 to 2003. J Am Coll Cardiol. 2005;46:2004. 246. Gawaz M, Neumann FJ, Ott I, May A, Schomig A. Platelet activation and coronary stent implantation: effect of antithrombotic therapy. Circulation. 1996;94:279-285. 247. Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:1773-1780. 248. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323. 249. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimusand paclitaxel-eluting coronary stents. N Engl J Med. 2007;356:998-1008. 250. Trikalinos TA, Alsheikh-Ali AA, Tatsioni A, Nallamothu BK, Kent DM. Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis. Lancet. 2009;373:911-918[Erratum, Lancet 2009;374:378.] 251. Food and Drug Administration (FDA) Update to FDA statement on coronary drug-eluting stentshttp://www.fda.gov/cdrh/news/010407.html. 252. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimusand paclitaxel-eluting coronary stents. N Engl J Med. 2007;356:998-1008. 253. Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings. J Am Coll Cardiol. 2006;47:2108-2111. 254. Newsome LT, Kutcher MA, Royster RL. Coronary artery stents: Part I. Evolution of percutaneous coronary intervention. Anesth Analg. 2008;107:552-569. 255. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol. 2008;52:333-342. 256. Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med. 2010;362:1663-1674.

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

2 0 1 1 H o u s e o f D e l e g at e s & A n n ua l S c i e n t i f i c M e e t i n g

June 20-25 What Every Physician Should Know About Disasters

Make a Capital Investment in Your Future

A t t e n d t h e 2 0 11 A n n u a l S c i e n t i f i c M e e t i n g

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

M e d i c a l E t h i c s Without the Rhetoric Cases presented here involve real physicians and patients. Unlike the cases in medical ethics textbooks, these cases seldom involve cloning, bizarre treatments, or stem cell research. We emphasize cases more common to the practice of medicine. Most cases are circumstantially unique and require the viewpoints of the practitioners and patients involved. For this reason, I solicit your input on the cases discussed here at councile@aol.com. Reader perspectives along with my own viewpoint are published in the issue following each case presentation. We are also interested in cases that readers submit. The following case touches on medical procedures which are not futile but are still questionable in terms of required resources.

Mark Pastin, PhD Mark Pastin, PhD, is president and CEO of the Council of Ethical Organizations, Alexandria, VA. The Council, a non-profit, nonpartisan organization, is dedicated to promoting ethical and legal conduct in business, government, and the professions.

case EIGHT

N E V E R TOO OLD F O R LO V E

The patient is an eighty-two year old male who is in excellent physical condition – except for his need for a kidney. Otherwise, he has the physical condition of a sixty-year-old. His wife who, in fact, is a sixty-year-old wants to donate a kidney to her husband. The medical professionals involved in the case believe that the organ could be successfully harvested and that the transplant might well extend the life of the husband. The wife is in good enough health to qualify as a donor in medical terms, but her age would generally disqualify her. The issues of the wife’s age qualification aside, the medical professionals involved have qualms about transplanting an organ for an eighty-twoyear-old person, even if the person is otherwise healthy. There is no question of who is going to pay as the couple is wealthy and will cover all costs. Some of the involved medical professionals even feel that there is something to be learned from performing a transplant in such an unusual case. Putting aside legal and regulatory concerns, is it ethically permissible to perform the transplant?

Medical Ethics Without the Rhetoric

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

M e d i c a l E t h i c s Without the Rhetoric CASE SE VEN A N ALYSIS

civil but disobedient

Our case from the last issue concerns a fourteen-year-old girl who was a victim of a disfiguring fire when she was in kindergarten. She has undergone numerous surgeries intended to address her disfigurements – but she is now refusing a surgery recommended by her physician and encouraged by her parents. Given that she is a minor, the surgery could probably proceed without her approval based on her parents’ permission, but the physician is uncomfortable proceeding. Reader opinion on this case was divided. Many argued that since the surgery is probably not medically necessary, the girl’s wishes should be honored. If there was medical urgency to the procedure, the physician might proceed on the basis of the parents’ wishes and permission. But not in this case. Others felt that the surgery should proceed especially since the girl, while opposed to the procedure, will accede to her patents’ wishes. The surgery is likely to be successful and the girl appreciative in the long run. As with many medical ethics cases, there is not a simple “yes” or “no” answer. My position is that the physician should honor the girl’s wishes in the short term on the condition that she and her parents seek counseling concerning her condition and her future options. The goal is to build the girl’s confidence in the physician and the many caregivers she will undoubtedly encounter in coming years. The hope is that she will go along with the surgery before too much times passes. But there is no guarantee that this will happen.

This is an actual case. Of course, there are any number of complicating circumstances and additional details; but please address the case on the basis of the information provided. There will be an analysis of this case and a new case in the next issue.

Medical Ethics Without the Rhetoric

American Journal of Clinical MedicineÂŽ â&#x20AC;˘ Winter 2011 â&#x20AC;˘ Volume Eight, Number One

Malignant and Benign Eyelid Lesions in San Francisco: Study of a Diverse Urban Population Sean Paul, MD Dat T. Vo, BS Rona Z. Silkiss, MD, FACS

Purpose To describe the incidence and epidemiology of primary eyelid tumors diagnosed in a diverse urban medical center in San Francisco from 2004-2007.

Design Retrospective eyelid pathology data review.

Participants A total of 855 primary eyelid tumors retrieved from the California Pacific Medical Center Surgical Pathology database between January 2004 and December 2007. All 855 were histopathologically verified and used for analysis.

Methods The histopathological diagnosis of benign and malignant eyelid tumors was stratified based on age, gender, ethnicity, and tumor location.

Main Outcome Measure Incidence of eyelid neoplasia.

Results The mean age of patients treated for an eyelid lesion was 60.1 years. Of the eyelid lesions 24.1% were malignant and 75.9% were benign. The most common eyelid malignancy was basal cell carcinoma (71.8%), followed by squamous cell carcino-

ma (9.7%), melanoma (9.2%), and sebaceous cell carcinoma (7.3%). The most common benign lesions were seborrheic keratosis (19.7%), followed by lipogranuloma (13.7%), intradermal nevus (12.2%), and hidrocystoma and fibroepithelial polyps (each with 8.6%).

Conclusions Eyelid tumors affecting an ethnically diverse population were studied. The data demonstrate an increased number of basal cell carcinomas among male patients relative to previous studies.1-4 This may be secondary to the increased incidence of HIV/ AIDS in the San Francisco area. The data also corroborate previous reports that Asian ancestry, though increased in the San Francisco area as well relative to other populations studied, is not a risk factor for developing sebaceous carcinoma outside of Asia.5

Introduction Eyelid lesions are common concerns amongst patients. Internists, family practitioners, dermatologists, and ophthalmologists are often requested to determine if a lesion is benign or malignant. Histopathological diagnosis and clinical correlation have been studied in published case reviews. Studies overseas have also examined the incidence in specific populations.1-3,6,7 Benign tumors greatly outnumber malignant tumors.1-5 Basal cell carcinoma has been shown to have the highest incidence among malignancies.8 Lin et al. described a significantly higher incidence of sebaceous gland cell carcinoma in Taiwan.1

Malignant and Benign Eyelid Lesions in San Francisco

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

In this case series review, the authors examined the incidence and histopathology of eyelid tumors in an American urban medical center with a diverse patient population. Eyelid tumor pathology data were gathered from the California Pacific Medical Center in San Francisco, California, from 2004 to 2007. The authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. While previous studies regarding eyelid tumors have relied on national tumor registries in various countries and regions within the United States, this study focused solely on eyelid tumors at a specific hospital in an urban setting with a known diverse population.

Materials and Methods California Pacific Medical Center (CPMC) provides pathology services for its four-hospital network and referring community physicians. Pathologists working at CPMC collect, process, and interpret pathology specimens. The reports are placed into an electronic database available to CPMC physicians. Items registered include the patient’s name, gender, age, location of tumor, and histopathogical diagnosis. The investigators of this study reviewed the data specific to eyelid tumors. Duplications in data entry were eliminated to aid in the accuracy of analysis. For this analysis, the authors examined eyelid tumor data between January 2004 and December 2007 from the CPMC pathology database under the search entry ‘eyelid.’

Table 1: Eyelid Tumors at California Pacific Medical Center from 2004-2007.

Tumor Type

Number

Malignant Lesions, n=206 (24.1%) Basal Cell Carcinoma

148

Squamous Cell Carcinoma

Melanoma

Sebaceous Gland Cell ca and variants

Other Cancers

Benign Lesions, n=649 (75.9%) Seborrheic keratosis

128

Lipogranuloma and Chalazion

Intradermal nevus

Hidrocystoma

Fibroepithelial polyp

Inclusion cysts (epidermoid)

Verruca Vulgaris

Actinic Keratosis

Other benign tumors

155

Total Lesions, n=855 Figure 1: Average Ages for Tumors (n>10).

Individual state tumor registries do not specifically track eyelid tumors and malignancies. The use of the CPMC registry allowed us a unique opportunity to study the spectrum of eyelid tumors in an urban population. This study received approval of the Institutional Review Board of California Pacific Medical Center.

Results A total of 855 people with eyelid lesions diagnosed from January 2004 to December 2007 were identified from the CPMC tumor database. There were 453 females (53.0 %), 400 males (46.8 %), and 2 (0.2 %) unspecified gender. Neither the ethnicity nor HIV status of the patients was specifically identified. Of these 855 cases, 206 were found to be malignant neoplasms and 649 were benign neoplasms (Table 1). The mean age was 60.1 years with a range of 1-96 years. Malignant tumors were diagnosed primarily in patients with an average age over 60, and most benign tumors, other than seborrheic keratosis and actinic keratosis, were diagnosed in patients under the age of 60 (Figure 1). There was no evident left-sided or right-sided preference seen amongst most tumors. However, squamous cell carcinoma and melanoma demonstrated a slight preference for the left eyelid. Seborrheic keratosis demonstrated a preference for the right eyelid.

Malignant Lesions In this study, eight different malignant lesions were reported. Basal cell carcinoma (BCC) was the most commonly diagnosed tumor (n=148) (Photo 1). BCC accounted for 71.8% of all malignant lesions and accounted for 17.3% of all lesions. While other tumors found in this study did not show evidence of gender preference, BCC occurred predominantly in men. The incidence of tumor presentation in men compared to women was 8.25:1

Malignant and Benign Eyelid Lesions in San Francisco

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Figure 2: Eyelid Lesions Per Gender.

(Figure 2). These data reveal a significant increase in reported BCC among male patients compared to previous studies (Table 2).1-4 This tumor also showed a preference for the lower eyelid in 132 of the 148 lesions.

Photo 2: Squamous Cell Carcinoma of the Lower Eyelid.

Photo 1: Basal Cell Carcinoma of the Lower Eyelid.

Photo Courtesy of Rona Z. Silkiss, M.D.

Table 2: Comparison of BCC by study.

BCC Male to Female Ratio Study

M:F Ratio

Taiwan (2006)1

1.3

Olmsted County, MN (1999)2

1.4

Finland (2005)3

1.1

Switzerland (2009)4

San Francisco (Current Study)

8.25

The second most common tumor was squamous cell carcinoma (SCC) with n=20 (Photo 2). SCC occurred in 9.7% of malignancies examined and represented 2.3% of all lesions. These tumors had a slight preference for the left eyelid, were evenly distributed between men and women, and were preferentially seen on the lower lid. Melanoma was the third most common malignancy with an n=19 (Photo 3). They accounted for 9.2% of all malignant eyelid lesions and 2.2% of all lesions reported. The cases of melanoma seen in this study favored female patients as well as the left side and the lower eyelid. The fourth most common malignancy was sebaceous gland carcinoma (SGC) with n=15 (Photo 4). This represented 7.3% of eyelid malignancies reported and 1.8% of all lesions. Patients with SGC did not show preference for eyelid side nor for gender, but showed a very strong preference for the upper eyelid.

Malignant and Benign Eyelid Lesions in San Francisco

American Journal of Clinical MedicineÂŽ â&#x20AC;˘ Winter 2011 â&#x20AC;˘ Volume Eight, Number One

Out of the 15 clinical samples, 86.7% of the tumors (n = 13) were located on the upper lid while only two, or 13.3%, were located on the lower lid. The preference for the upper lid is linked to an increased number of meibomian glands located in the upper lid (30) versus the lower lid (20).9, 10

Photo 5: Chalazion of Bilateral Eyelids.

Other cancers of note in this study included malignant B cell lymphoma n=2, Merkel cell carcinoma n=1, and an adnexal malignant tumor n=1. Photo 3: Melanoma of the Lower Eyelid.

Photo Courtesy of Rona Z. Silkiss, M.D.

Chalazion (n=89) accounted for 13.7% of all benign lesions (Photo 5). These were evenly distributed between men and women as well as on the right and left sides. There was a slight preference for the lower eyelid in this study. Lesions in this groups included chalazions, which are lipogranulomas of the meibomian glands or glands of Zeis. Intradermal nevus (n=79) represented 12.2% of all benign lesions (Photo 6). Lesions examined in this study were diagnosed more often in female patients and were found predominantly on the lower eyelid. There was no right- or left-sided preference.

Photo Courtesy of Rona Z. Silkiss, M.D.

Photo 4: Sebaceous Gland Carcinoma of the Upper Eyelid

Photo Courtesy of Rona Z. Silkiss, M.D.

Photo 6: Intradermal Nevus of the Lower Eyelid

Photo Courtesy of Rona Z. Silkiss, M.D.

Benign Lesions

Photo 7: Hidrocystoma of the Lower Eyelid.

Benign lesions accounted for 75.9% of all tumors in this study. The average age of individuals diagnosed with a benign lesion was less than 60 years. There were numerous types of benign lesions; those with over ten occurrences are described in this study. Seborrheic keratosis was the most common benign neoplasm of the eyelid with n=128, representing 19.7% of benign lesions. These lesions were seen equally in male and female patients, demonstrated a preference for the upper lid and location on the right side. These have been reported in multiple studies as the most common benign tumor in older individuals. This was substantiated by the CPMC experience.

Photo Courtesy of Rona Z. Silkiss, M.D.

Malignant and Benign Eyelid Lesions in San Francisco

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Hidrocystomas (n=56) represented 8.6% of benign lesions (Photo 7). Most of the lesions examined in this study were found on the lower lid. Side or gender preference was not demonstrated. These are cysts of the sweat glands including eccrine, sebaceous, and apocrine subtypes. Fibroepithelial polyps (n=56) represented 8.6% of all benign lesions. There was a slight preference for the right eyelid, and most cases were diagnosed in males. There was an even distribution of this lesion on both the upper and lower eyelids. These are also known as acrochordons and skin tags. Inclusion (epidermoid) cysts (n=46) demonstrated a slight preference for the right eyelid, but no gender or upper or lower eyelid preference was seen. These accounted for 7.1% of benign tumors. Verruca vulgaris (n=22) are virus-borne lesions commonly known as warts. These accounted for 3.4% of benign lesions. Most of these cases were seen in female patients and on the left eyelid. There was an even distribution on both the upper and lower lids. Actinic keratosis (n=18) are pre-malignant lesions that accounted for 2.8% of benign lesions (Photo 8). These lesions, unlike most of the other benign lesions, had a mean age over 60. There was a strong preference for these lesions to be seen on the lower lid, and most cases were on the right side. There was no gender preference. Photo 8: Actinic Keratosis of the Eyelid.

on data from the US Census Bureau in 2007, the San Francisco county population was comprised of 57.7% Whites, 31.6% Asian Americans, 14.0% Hispanic/Latinos, 6.9% Blacks, 2.7% Multi-racial, and 0.5% Native Americans.11 Note that, as some census takers reported multiple races, the total is over 100%.10 This population contrasts with previous studies in which largely homogenous populations were studied (i.e., Taiwan, Minnesota, and India).1,12,13 An important consideration in this study is that data were retrieved from the pathology logs of CPMC due to limitations from individual states and cities in the United States not keeping formal records of eyelid tumors. Studies referenced in this paper retrieved their data from a variety of sources including national and local cancer registries as well as hospital pathology laboratory data (Table 3). The authors still believe that this study shows an interesting overview of data from a busy, community hospital, caring for a diverse urban population that is important for ophthalmologists and other physicians. Table 3: Eyelid Tumor Study Data Retrieval Sources.

Study

Data Retrieval

Taiwan

Taiwan National Cancer Registry

Olmsted County, MN2

Olmsted County, Minnesota Computerized retrieval system

Finland3

Finnish Cancer Registry

Switzerland4

Laboratory of Ophthalmopathology of the Hôpital Ophtalmique Jules Gonin, Lausanne, Switzerland

Singapore6

Singapore Cancer Registry

Florida

Florida Cancer Data System

India

NCI Sebaceous Gland Cancer5

Photo Courtesy of Rona Z. Silkiss, M.D.

There were 155 additional benign lesions of which there were n<10. This accounted for 23.9% of benign lesions and 18.1% of all lesions in the study. Examples of lesions included in this group are: sebaceous adenoma, benign capillary hemangioma, molluscum contagiosum, lipoma, milia, and syringoma.

Discussion Using the data from the CPMC pathology database, the authors examined the characteristics of eyelid lesions in the diverse San Francisco community. To our knowledge, this is the first study of the distribution of eyelid lesions in a richly diverse ethnic US population. Based

Ocular Pathology Records National Cancer Institute’s Surveillance, Epidemiology, and End Results database

The authors report an increased incidence of basal cell carcinoma in the male population. Factors that may explain the increase of basal cell carcinoma of the eyelid of this population include: the higher incidence of HIV/AIDS (26 cases per 100,000 persons in San Francisco County versus 12.5 cases per 100,000 persons in the United States in 2007),14 sun exposure as well as increased public awareness of disease presentation, surveillance, and better diagnostic and reporting techniques. In general, the popularity of cosmetic surgery may contribute to the increased incidence of eyelid tumor diagnosis even among men and minorities. In 2007, the American Society for Aesthetic Plastic Surgery reported that the number of both surgical and nonsurgical cosmetic procedures performed on men increased 17%. Twenty-two percent of the aesthetic procedures were performed on racial and ethnic minorities between 2006 and 2007.15

Malignant and Benign Eyelid Lesions in San Francisco

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Our study confirms that the incidence of malignant eyelid lesions increases with age. While some of the lesions showed left- or right-side preferences, we were unable to provide reasons for whether a lesion presented on the left or right except for those lesions induced by sun exposure. Left-side preference when it occurs (i.e., melanoma) may be related to sun exposure specifically while driving. This phenomenon has been studied in truck drivers in Turkey where there is an effect of increased ultraviolet light exposure on one side of the face.16 In agreement with other published studies, BCC was the most common malignancy reported. In contrast to other studies demonstrating an equal male/female distribution, our data demonstrated a significant difference in the number of men diagnosed over women with basal cell carcinoma.2 We believe that this may be due to the higher use of sunscreen by women, the use of occlusive makeup or sunscreen containing makeup in women, the culture of sun bathing and water sports among men and the higher number of men with HIV/AIDS in the San Francisco community.14 These data were corroborated by a report of HIVinfected patients with non-melanoma cancers in San Francisco in the early 1990s.17, 18 In 2007, at the Fourth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, a study evaluating the incidence of skin cancer in HIV patients in the United States demonstrated a rate of BCC (200 cases per 100,000 PY) that was 2.3-fold higher than that seen in the HIV-negative population. The rate of melanoma was elevated by 3.1-fold compared with the general population.14 Additionally in 2009, Crum-Cianflone et al. reported that with the advent of highly active antiretroviral therapy (HAART), the incidence rates of cutaneous non-AIDS-defining cancers, in particular basal cell carcinoma, exceeded the rates of cutaneous AIDS-defining cancers such as Kaposi sarcoma.19 Thus, we postulate that a relationship exists between the increased basal cell carcinomas among male patients seen in the San Francisco County population with a relatively higher number of HIV/AIDS patients. Interestingly, while most other studies describing basal cell carcinoma distribution showed nearly a 1:1 male to female ratio, Deprez et al. saw a significantly higher ratio of male to females with a diagnosis of basal cell carcinoma (25:1) in the Swiss population. While this sig-

nificant finding was not discussed directly in their study, Switzerland has the highest adult prevalence of HIV/AIDS cases in the adult population in Western Europe (0.6%), which could explain this finding and support our hypothesis. Increased numbers of sebaceous gland carcinoma were seen in the Taiwanese and Indian populations.1, 12 This was not seen in the San Francisco population despite including a significantly higher Asian population than other parts of the United States (Table 4). These results confirmed a recent study by Dasgupta et al. that concluded that established Asian/Pacific Islander ancestry is not a risk factor for developing sebaceous carcinoma.5 Table 4: Asian Population Demographics in United States and Taiwan.

City

Percentage Asian Race

SF, CA

31.3

Olmstead County, MN

LA, CA

10.4

NYC, NY

11.8

Houston, TX

5.3

Atlanta, GA

1.9

Miami, FL

0.8

Raleigh, NC

3.8

Boston, MA

8.2

Denver, CO

3.3

Chicago, IL

4.9

St. Louis, MO

Dallas, TX

2.5

Ethnic Groups in Taiwan

Percentage

Taiwan

Mainland Chinese

Indigenous

Table 5: Comparison of Eyelid Studies.

Study

Years Study Conducted

Sample Size (n)

Length of Study (years)

Average Cases/ Year

San Francisco (current study)

2004-2007

855

213.8

Taiwan

1980-2000

1166

55.5

Olmsted County, MN

1976-1990

174

11.6

Finland

1 2

1953-1997

6241

141.8

Switzerland4

1989-2007

5504

305.8

Singapore

1968-1995

325

12.0

1981-1994

206

15.8

1982-1992

313

31.3

Florida India

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Studying the San Francisco population revealed a significant increase in incidence of eyelid tumors found compared to previous studies other than Deprez, et al., who interestingly observed more cases per year in the Swiss population (Table 5).1-4, 6, 7,13 The current findings may be due to increased awareness of and screening for skin tumors as well as the economic ability of patients to care for these lesions. Observed as well were an increased number of men with basal cell cancer in a population with an increased number of HIV patients. The authors conclude that skin cancer screening is recommended in a known population with an increased incidence of HIV/AIDS. We acknowledge the limitations of this study. Specifically, various pathologists reviewed the slides over the several year interval. The authors concede that this study may not represent the entire San Francisco population and that, without national and state registries, it is nearly impossible to do so. Nonetheless, this study provides an interesting overview of eyelid neoplasia in a diverse urban population which displays important changes in epidemiological characteristics in a specific United States population. Sean Paul, MD, Department of Ophthalmology, University of Oklahoma, Dean McGee Eye Institute, Oklahoma City, Oklahoma. Dat T. Vo, BS, Greeney Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio. Rona Z. Silkiss, MD, FACS, California Pacific Medical Center, San Francisco. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The authors have stated that no such relationships exist. ®

References

Deprez M, Uffer S. Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature. Am J Dermatopathol. May 2009;31(3):256-262.

Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. Jan 1 2009;115(1):158-165.

Lee SB, Saw SM, Au Eong KG, Chan TK, Lee HP. Incidence of eyelid cancers in Singapore from 1968 to 1995. Br J Ophthalmol. May 1999;83(5):595-7.

Margo CE, Mulla ZD. Malignant tumors of the eyelid: a population-based study of non-basal cell and non-squamous cell malignant neoplasms. Arch Ophthalmol. Feb 1998;116(2):195-8.

Prabhakaran VC, Gupta A, Huilgol SC, Selva D. Basal cell carcinoma of the eyelids. Compr Ophthalmol Update. Jan-Feb 2007;8(1):1-14.

Awan KJ. Sebaceous carcinoma of the eyelid. Ann Ophthalmol. May 1977; 9(5):608-610.

10. Song A, Carter KD, Syed NA, Song J, Nerad JA. Sebaceous cell carcinoma of the ocular adnexa: clinical presentations, histopathology, and outcomes. Ophthal Plast Reconstr Surg. May-Jun 2008;24(3):194-200. 11. US Census Bureau. San Francisco County, California Census Data. Available at: http://quickfacts.census.gov/qfd/states/06/06075.html. Accessed March 23, 2010. 12. Wang JK, Liao SL, Jou JR, et al. Malignant eyelid tumours in Taiwan, Eye (Lond). Mar 2003; 17(2):216-220. 13. Sihota R, Tandon K, Betharia SM, Arora R. Malignant eyelid tumors in an Indian population. Arch Ophthalmol. Jan 1996;114(1):108-9. 14. Department of Health and Human Services, Centers for Disease Control and Prevention. Reported AIDS cases and annual rates. Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2007report/ table17.htm. Accessed March 23, 2010. 15. American Society for Aesthetic Plastic Surgery. ASAPS News Release Feb 2008. Cosmetic Procedures in 2007. Available at: http://www. cosmeticplasticsurgerystatistics.com/statistics.html#2007-NEWS. Accessed March 23, 2010. 16. Kavak A, Parlak AH, Yesildal N, Aydogan I, Anul H. Preliminary study among truck drivers in Turkey: effects of ultraviolet light on some skin entities. J Dermatol. Mar 2008;35(3):146-150. 17. Lobo DV, Chu P, Grekin RC, Berger TG. Nonmelanoma skin cancers and infection with the human immunodeficiency virus. Arch Dermatol. May 1992;128(5):623-7.

Lin HY, Cheng CY, Hsu WM, Kao WH, Chou P. Incidence of eyelid cancers in Taiwan: a 21-year review. Ophthalmology. Nov 2006;113(11):2101-7.

18. National AIDS Manual. IAS: Skin cancers more common among HIVpositive people, screening recommended. http://www.aidsmap.com/ en/news/6C45D201-3C3D-4DC6-838D-208B30611703.asp. Accessed March 23, 2010.

Cook BE, Jr, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County, Minnesota. Ophthalmology. Apr 1999;106(4):746-750.

19. Crum-Cianflone N, Hullsiek KH, Satter E, et al. Cutaneous malignancies among HIV-infected persons. Arch Intern Med. Jun 22, 2009;169(12): 1130-8.

Paavilainen V, Tuominen J, Pukkala E, Saari KM. Basal cell carcinoma of the eyelid in Finland during 1953-97. Acta Ophthalmol Scand. Apr 2005;83(2):215-220.

20. AVERT. European HIV and AIDS Statistics. Available at: http://www. avert.org/hiv-aids-europe.htm. Accessed March 23, 2010.

Malignant and Benign Eyelid Lesions in San Francisco

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Invasive Squamous Cell Carcinoma of the Cervix Following HPV Immunization in a Nineteen-Year-Old Woman Daniel M. Avery, Jr., MD, FAASS Dwight Hooper, MD, MBA

Abstract The incidence of cervical cancer is very low in the United States. The American College of Obstetricians and Gynecologists’ (ACOG) recommendations suggest cervical cancer screening (Pap tests) beginning at age 21 regardless of when sexual activity may have begun. However, there are a few young women who will develop cervical cancer. This paper presents a case of invasive cervical cancer in a 19-year-old female who had previously received the HPV vaccine series. The incidence of cervical cancer continues to decrease with the current screening methods.1 Cervical cancer is still the second most common cancer in women worldwide.2,3 There are an estimated 11,270 new cases of cervical cancer along with 4,000 deaths in the United States annually.1 Worldwide, there are about 500,000 cases and 270,000 deaths annually.2 Human papillomavirus (HPV) infections are the most common sexually transmitted disease in this country; there are 20,000,000 American that are infected.4 Six million people in this country become infected with the virus yearly.4 Human papillomavirus infections are obtained after their sexual debut, but natural immunity in most healthy young women clears the infection within two years.1 HPV infections are greatest in young women and decrease with ensuing age.2 Most infections are asymptomatic.5 Dysplasia is common in adolescents but most clears spontaneously.1 The HPV vaccine is effective immunologically against HPV types 16 and 18 but may not protect against other types.1,6 Approximately 30% of cervical cancer is caused by other HPV

types.1 Currently there are 120 types of HPV.2,5,7 Previous infections with HPV do not confer lasting immunity.8 Persistent infection with an HPV is necessary for the development of cervical cancer.8 The ACOG Guidelines recommend initiating screening at age 21 years regardless of age of sexual debut; then screening every other year until age 29.1 The incidence of cervical cancer in women younger than 21 years is 0.1%.1 The American College of Obstetricians and Gynecologists reported 14 cases of cervical cancer in females aged 15 to 19 with an incidence of one to two women with cervical cancer in 1,000,000 females.1,5 Beller and Abu-Rustum reported two cases of cervical carcinoma in 2009.9 One of the cervical cancers was a poorly differentiated type with clear cell features on histological examination and was unrelated to HPV.9 The other cancer was caused by HPV type 31 and not covered by the HPV vaccine.9 The following is a case of invasive squamous cell carcinoma of the cervix in a 19-year-old woman who had received the HPV vaccine at age 16.

Case Report A 16-year-old female presented with her mother to get the HPV immunization series. She received the complete series of three shots. The following year she presented for prenatal care. A Pap test was performed as part of the prenatal profile; the results were mild dysplasia. Following delivery of her baby, a Pap test was performed as part of her postpartum check-up. The results

Invasive Squamous Cell Carcinoma of the Cervix

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

were Atypical Squamous Cells of Undetermined Significance – HPV High Risk sub-type negative. Following the guidelines, she was asked to return in one year for repeat Pap test. She did not return nor have a Pap test anywhere else. The following year, a Pap test was performed by a nurse practitioner at a rural clinic. The results were Atypical Squamous Cells- cannot rule out high grade-lesion. She was referred for colposcopy. The patient had recently married and was hoping for another child. Colposcopic examination suggested a high-grade lesion, confirmed by cervical biopsies showing carcinoma-in-situ (possibly early invasive squamous cell carcinoma). Loop electrosurgical excision procedure performed in our office showed micro-invasive squamous cell carcinoma. She was referred to a gynecologic oncologist for consultation. A repeat cervical conization was performed showing invasive squamous cell carcinoma. A radical hysterectomy with pelvic and peri-aortic lymph node dissections was performed. The pathology report revealed moderately to poorly differentiated squamous cell carcinoma. No residual disease was present, and the lymph nodes were negative for tumor. The patient did well postoperatively. The long-term prognosis is excellent, although, of course, she cannot have more children. Cervical cancer unfortunately does occur in young women less than 20 years of age. The ACOG Guidelines do not recommend beginning pap smears until age 21 regardless of age of sexual debut so traditional screening can miss the few cases. The case presented does not meet the recommendations for Pap test screening as above but was diagnosed by a Pap test as part of prenatal care initial studies. At the time the standard of care was initiating Pap tests three years after beginning sexual activity. With the current recommendations, Pap testing would not have been performed in this young woman. Current explanations for cervical cancer in young women following HPV vaccination include: • Approximately 30% of cervical cancer is caused by HPV types other than 16 and 18.1 • Some cervical cancers are unrelated to HPV infections altogether.9 • Adenocarcinoma of the cervix is unrelated to HPV.9

Postcoital bleeding or spotting, multiple sexual partners, and other high-risk factors may alert the physician that enhanced cervical cancer screening may be appropriate for the patient. Daniel M. Avery, Jr., MD, FAASS, is Professor and Chairman, OB/GYN Department at The University of Alabama School of Medicine. Dwight E. Hooper, MD, is Associate Professor, OB/GYN Department at the University of Alabama School of Medicine. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The authors have stated that no such relationships exist. ®

References 1.

American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. 114 (6):1409-1420, Dec., 2009.

Kjaer SK. Human Papillomavirus (HPV) Infection, Cervical Cancer and Vaccination Against HPV: A Nordic Perspective. Acta Obstetricia et Gynecologica. 2009;86:1286-1289.

Sigurdsson K, Sigvaldason H, Gudmundsdottir T, Sigurdsson R, Briem H. The Efficacy of HPV 16/18 Vaccines on Sexually Active 18-23 Year Old Women and The Impact of HPV Vaccination on Organized Cervical Cancer Screening. Acta Obstetrica et Gynecologica. 2009;88:27-35.

Heavey E: Start Early to Prevent Genital HPV Infection—and Cervical Cancer. Nursing. 2008;May, 62-63.

Guido R: Human Papillomavirus and Cervical Disease in Adolescents. Clinical Obstetrics and Gynecology. 2008;51(2):290-305.

Franceschi S, Clifford GM. Fraction of Cervical Neoplasias Due to Human Papillomavirus 16 and 18 in Vaccine Trials. Letter to the Editor. Int J Cancer. 2008;122:719-720.

Ault KA. Human Papillomavirus Vaccines: An Update for Gynecologists. Clinical Obstetrics and Gynecology. 2008;51(3):527-532.

Bayas J-M, Costas L, Munoz A. Cervical Cancer Vaccination Indications, Efficacy and Side-Effects. Gynecologic Oncology. 2008;110:S11-S14.

Beller U, Abu-Rustum NR. Cervical Cancers After Human Papillomavirus Vaccination. Obstet Gynecol. 2009;113:550-552.

10. Castle P. Cervical Cancers After Human Papillomavirus Vaccination. Letter to the Editor. Obstet Gynecol. 2009;114(1):174;July, 2009. 11. Joura EA, Garland SM. Cervical Cancers After Human Papillomavirus Vaccination. Letter to the Editor. Obstet Gynecol. 2009;114(1):174175;July, 2009.

• Interval after vaccination may be unknown.10,11 • Vaccination may not be as effective as those vaccinated before sexual intercourse.5 • Cervical cancers related to currently undiscovered HPV types.7 • Poorly differentiated cancers may not have a relationship to HPV types. Physicians who care for adolescent females should be aware of the ACOG Guidelines but at the same time realize that there are a few young women that will develop cervical malignancies. Invasive Squamous Cell Carcinoma of the Cervix

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Abstract

Participants

Background

Internal medicine (IM) residents and attending physicians.

The majority of patients with chronic hepatitis C virus (HCV) infection remain undiagnosed. Studies have shown that primary care providers (PCPs) lack knowledge about HCV and do not comply with current practice guidelines for identifying and screening individuals at risk.

Measurements

Objective The aim of this study is to assess whether a multi-faceted intervention directed at PCPs (internal medicine residents and attending physicians) could improve knowledge about HCV risk factors and indications for screening and improve markers of patient care.

Design Controlled trial of a multifaceted intervention directed at PCPs.

Setting Three general internal medicine clinics in southeastern Michigan. Interventions were applied to two of the clinics and the third, affiliated with the community hospital training program, served as the control clinic.

A validated survey to measure knowledge about HCV risk factors, screening, and treatment of HCV, administered before and after the intervention to physicians from the intervention clinics; a structured retrospective review of outpatient records, from before and after the intervention, to measure and compare compliance with screening guidelines for HCV in the intervention clinics.

Intervention A six-week multi-faceted intervention consisting of educational articles, lectures, quizzes, and chart prompts.

Results of Survey Sixty out of 76 physicians completed both the pre- and postintervention knowledge survey. There were improvements in understanding the role of the PCP in screening and referral, in recognizing some important risk factors for HCV such as blood product transfusion before 1992 and IV drug use, but not sexual exposure or history of hepatitis B. Respondents were more confident in the post-intervention surveys of their knowledge of risk

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factors, diagnostic testing, and when to refer. They did not report significant changes in the way they practice except regarding routine care offered to patients with HCV.

Results of Record Review Patient records numbering 1285 were studied before the intervention and 703 after. There was significant improvement in the intervention clinics with respect to eliciting risk factors after the intervention. No change was noted in the control clinic. Overall, residents demonstrated greater improvement than the attending physicians.

Conclusions The multifaceted educational intervention improved several aspects of physician knowledge about HCV and was associated with a significant change in physician practice.

Introduction Approximately 4.1 million Americans (1.6%) have antibodies for the hepatitis C virus (HCV).1 Based on The National Health and Nutrition Examination Surveys (NHANES III), 2.7 million Americans are chronically infected and account for 40% of the chronic liver disease cases in the United States.2 Cirrhosis due to HCV is one of the most common indications for liver transplantation.3 Despite the impact of this disease and the multiple advances in knowledge regarding diagnosis, natural history, and treatment, the majority of HCV patients remain undiagnosed.4 Many professional societies and government agencies, including the American Association for the Study of Liver Diseases (AASLD), Center for Disease Control (CDC), National Institute of Health (NIH), and the American College of Preventative Medicine have endorsed routine screening of patients with risk factors.5,6 While these groups recommend screening in high-risk populations, they differ in their definition of this population. The AASLD and CDC agree that intravenous drug use (even remote or one-time use), blood and organ transplants, occupational exposure, children of HCV mothers , HIV positive individuals, individuals receiving clotting factors prior to 1987, individuals with persistently elevated ALT are all patients that should be tested. In addition, AASLD also recommends that patients with a history of hemodialysis and long-term spouse/ household contact with HCV are risk factors for transmission. NIH limits its definition of the high- risk population as individuals who have used intravenous drugs (even remote or one-time use), received blood and organ transplants, had multiple sexual partners, live with long-term spouse/household contact with HCV, and those who use intranasal cocaine or share a straw. While it may be difficult to inquire about risk factors on each visit, it is recommended that all new patient visits and health maintenance examinations should include HCV risk assessment. If any of the risk factors are present on inquiry and the patient has not been tested since the risk factor was identified, it is recommended that the patient has HCV screening test.

The expected benefits of early diagnosis include: modification of high-risk behaviors thought to hasten progression of the disease, modification of transmission risk, and early access to treatment. In addition, patients now have a greater than 40% probability of eradication with treatment. HCV is usually diagnosed at an advanced stage of liver disease. This is probably because the disease can remain asymptomatic for years. Physicians and patients lack knowledge about the disease and its risk factors, and patients fail to acknowledge high-risk behaviors. Previous studies have shown significant knowledge deficits and suboptimal management of HCV by primary care physicians (PCPs).7-9 Due to knowledge deficits, health care providers are also unaware of the benefits of early diagnosis to their patients. In a study reviewing primary care management, only 1% of physicians documented that they inquired about HCV risk factors during a health maintenance exam. Other research has shown most testing was based on evidence of liver damage, such as elevated transaminases, rather than recognition of HCV risk factors (less than 20%).10,11 With expert opinion favoring early screening and intervention but research indicating a lag in clinical practice and knowledge, we felt an educational intervention could potentially bridge knowledge gaps regarding recent guidelines and result in better physician practices regarding HCV. Historically, simple interventions to change physician behavior or practice have not been successful.12 In 1989 Eisenberg recommended utilizing six integral components to change physician behavior: education, feedback, financial reward, financial penalty, administrative change, and physician participation.13 Although not all aspects are necessary for success, the rate increases with the number of modalities in the intervention. Those with at least three modalities improved behavior in an average of 71% of participants, but even these more complex programs have not been uniformly successful.14,15 Typically, physician behavior has been shown to return to pre-intervention baseline typically by six months to one year. Hence, systems that utilize reminders in addition to components Eisenberg has described have the best chance for sustained change. In the past, routine interventions have failed to improve HCV screening and diagnosis in the primary care setting.9,11 In an attempt to address this situation, we designed and implemented a multifaceted intervention directed at PCPs and internal medicine residents to improve their knowledge about HCV risk factors, indications for screening, and referral and treatment options. The aims of this study were: 1) to measure the impact of this intervention on physician knowledge about HCV and 2) to measure the impact of this intervention on how patients are screened for HCV in clinical practice.

Methods Study Design & Subjects This study was a non-blinded controlled clinical trial with a before and after comparison of outcomes. The subjects of this

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

intervention were primary care teaching faculty and IM residents at St. Joseph Mercy Hospital (SJMH), a 529-bed teaching hospital located in Ann Arbor/Ypsilanti, Michigan. The Institutional Review Board at SJMH approved the study. Two intervention clinics, A and B, and one control clinic, C, were chosen because of their affiliation with the IM training program at our institution. Clinics A and C are faculty clinics with no resident participation and Clinic B is primarily a resident clinic under direct faculty supervision. The PCPs (residents and attending) were assigned to only one of the three clinics with no overlap. Appendix A: Structure of Clinical Intervention Trial(PHQ-9).

cluded the distribution of two HCV review articles to all the physicians in the two intervention clinics. There was also one HCV-focused morning report aimed at the IM residents, where appropriate evaluation of HCV in the outpatient setting was emphasized. We sponsored two one-hour interactive noon conference lectures about HCV screening and testing, where attendance by residents was mandatory, and many attending physicians from the intervention clinics participated. In addition, we supplemented this educational program with instructive weekly emails (web resources which were followed by trivia games with non-monetary prizes) to all physicians in the intervention clinics (Appendix A). The reminder system, which was in place during the chart review period, consisted of 5x7 inserts printed on fluorescent pink stickers, containing six specifically worded questions regarding the most common HCV risk factors (Appendix B). These prompts reminded physicians to inquire about HCV risk factors and to offer testing for HCV if any of the responses were positive.

Pre- and Post-Intervention Physician HCV Knowledge Assessment

Appendix B: (Pink Chart Prompts) Screening Inquiries for Hepatitis C Risk Factors.

(Pink Chart Prompts) Screening Inquiries for Hepatitis C Risk Factors

One week before the start of the intervention and one month after it was completed, we administered a 30-question, validated survey,16 consisting of multiple choice questions and clinical vignettes to all attending and IM resident physicians from the intervention clinics. This survey addressed HCV risk factor identification, current HCV diagnostic testing options, and options for the care and referral of HCV positive patients. Appendix C: Structure of Study Clinics.

1. Did you ever have a transfusion of blood or blood products before 1992? 2. Have you ever been told you have problems with your liver or liver blood tests? 3. Have you had any sexual contact with a person who had or you believe may have had hepatitis C? 4. Have you ever, even once, used a needle to inject recreational drugs? 5. Have you ever had a job where you were exposed to blood or body fluids? 6. Have you ever, even once, snorted cocaine of other recreational drugs?

Intervention An eight-week long intervention consisting of an intense educational program and a reminder system was initiated one week after the administration of the baseline knowledge assessment survey. The components of the educational intervention in-

Pre- and Post-Intervention Physician HCV Chart Review We completed medical record reviews and data abstraction for a total of 1285 patient visits in the six months prior to the intervention and 703 patient visits after the intervention. We reviewed the records of all patients seen by residents during these periods and every third patient of the attending physicians. This included approximately 30 to 40 patients assigned to each attending physician, and four to 30 for each resident in each time period. There were five physicians represented from clin-

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ic A, and 46 from clinic B, including 40 residents (Appendix C). When the study was designed, there were four physicians from clinic C; however, two of them left the practice before the evaluation was completed, and their patients did not contribute to the analysis. Members of the research team, including an IM resident, a research assistant, and a gastroenterologist, abstracted the data from medical records and laboratory databases, using a previously designed structured data collection tool (available on request). This information included patient demographics, clinic, type of physician (resident versus attending), previous testing for HCV, documentation of presence or absence of HCV risk factors (Appendix B), and whether HCV serology was ordered.

Statistical Methods All statistical analyses were done using SAS® 9.1. Baseline physician and patient characteristics were summarized using means and percentages as indicated. Responses to the survey questions were summarized using means and percentages, as appropriate.

Survey Analysis All responses were analyzed as repeated measures. We used the non-parametric signed rank test for questions answered on a

Likert scale and McNemar’s test for binary responses. Statistical significance was set at 0.05, throughout.

Analysis of record review Differences between clinics was tested using Wilcoxon Rank Sum test for scalar variables and Chi-square test for categorical variables. Two major outcomes were defined to compare compliance with risk factor screening in patients seen in the clinics, before and after the intervention. The first outcome was positive if any HCV risk factor was documented and the second outcome was positive if all six risk factors were documented. We used generalized estimating equations with physician of record as a random effect, and then tested whether the intervention, clinic, physician type (attending or resident), or age, gender, race, or insurance status of the patient influenced outcome. We also tested the interaction between the intervention and physician type and the intervention and clinic to see whether there was a difference in response to the intervention between residents and attendings and between clinic A and Clinic B. Odds ratios were reported for all independent variables that reached statistical significance, set at 0.05. We also reported the percent of patients at each clinic, before and after the intervention, with a HCV test ordered, and the percent positive for that test.

Table 2: Changes in HCV Knowledge Questionnaire.

Question Big problem to society Role of PCP Screening Diagnosis Monitoring Treat with antivirals Referral for all management Referral for co-management Reasons to test Blood Transfusion before 1992 Blood Transfusion after 1992 History of IVDU Tattoos Sex Partner with HCV Prenatal Abnormal LFT Hemodialysis HBV HIV Level of confidence Knowledge risk factors Knowledge diagnostic tests Knowledge monitoring Deciding when to refer Ability to give antivirals Community incidence

Mean value on pre-test scale 1-5

Mean difference between pre and post-test scales

p-value Signed rank test for paired differences

3.41

0.05 + means more likely to agree 0.25 -0.08 -0.19 -0.13 -0.36 0.10 + means more likely to test 0.56 -0.26 0.31 0.06 0.02 0.25 0.04 0.27 0.20 0.27 + means more confident 0.45 0.36 0.51 0.34 0.27 0.34

0.64

4.33 4.53 4.00 2.70 3.28 4.20 2.99 1.60 3.46 2.53 3.29 1.87 3.15 1.98 3.17 3.28 3.72 3.39 2.78 3.36 1.56 2.87

0.02 0.47 0.27 0.41 0.02 0.38 <0.01 0.17 <0.01 0.80 0.95 0.09 0.99 0.11 0.15 0.03 <0.01 <0.01 <0.01 0.03 0.06 0.07

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Results Survey Data Seventy-one pre-intervention and 63 post-intervention surveys were completed. Sixty physicians completed both the pre- and the post-intervention surveys and were included in the repeated measures analysis. At baseline, the mean age of the 54 respondents who provided a birth year was 34. On average, surveyed physicians were 5.5 years out of medical school. Fifty-two percent were female, 14% were attending physicians, and 80% practiced at the academic internal medicine clinic. Table 2 shows the results of questions scored on a Likert scale concerning the role of the PCP in eliciting risk factors, testing for HCV, and caring for patients with HCV. From the pre- to the post- intervention periods, physicians were more likely to agree that the role of the primary care physician was to screen for risk factors and less likely to agree that the PCP should refer to a specialist for all HCV management decisions; p = 0.02 and 0.02, respectively. Agreement with other roles for the PCP in HCV diagnosis, monitoring, treatment, and referral did not change. Surveyed physicians were more likely to test for HCV after the intervention under three conditions: blood transfusion before 1992, history of IV drug use, and patients who are HIV positive; p= 0.01, 0.01, and 0.03, respectively. There was no change in their likelihood of testing for tattoos, pregnancy, hemodialysis, sexual exposure, alcoholism, hepatitis B, or abnormal liver function tests. Their level of confidence about their knowledge of risk factors, diagnostic tests, monitoring, and deciding when to refer, improved after the intervention; p< 0.01, 0.01, 0.01, and 0.03, respectively. Table 3 shows the percentage of physicians who endorsed various practice patterns before and after the intervention, and the results of McNemar’s test for paired comparisons. Fifteen percent more physicians reported using a standard risk sheet (p<0.05) and 18% more reported that they asked all new patients about risk factors (p=0.04). Post-intervention, 7% percent more physicians were incorrectly choosing RIBA testing to screen for HCV (p<0.05). Physicians reported that 44% more would council HCV patients to avoid alcohol (p<0.01), and 36%, 43%, and 27% more would routinely order HBV, HIV, and syphilis testing, respectively, for their HCV patients (p<0.01, 0.01 and 0.05, respectively). For the majority of practice choices, however, physicians did not report a change in behavior.

Chart Review Data A total of 1285 patients were studied before the intervention, 203 from Clinic A, 978 from Clinic B and 104 from Clinic C. After the intervention, 703 patients were studied, 150 from Clinic A, 465 from Clinic B and 88 from Clinic C. Residents saw 78% of patients studied in Clinic B. A comparison of patient characteristics between the clinics is shown in Table 1. The clinics differed significantly in their patient mix. Clinic A patients were more likely to be older, female, and white. Clinic B patients were more likely to have no insurance and to be new

to the practice. At baseline, Clinic B physicians were much more likely to ask about any hepatitis C risk factors than physicians at the other clinics. Table 1: Characteristics of 60 participants completing both surveys.

CHARACTERISTIC Gender Male Female Professional Ranking Attending Resident Current number HCV patients 0 1-5 6-10 >10 New HCV patients in the past year 0 1-5 6-10 >10

Percentage 48 52 18 82 34 50 14 2

64 36 0 0

Table 5 summarizes the screening and testing results for all three clinics before and after the intervention. No risk factor screening was done for any patient at Clinic C either before or after the intervention. There appeared to be an increase in partial and complete screening for risk factors in both clinics A and B after the intervention. In the pre-intervention phase, twelve tests for HCV were ordered, eleven in Clinic B (1.1%) and one in Clinic A (0.5%). After the intervention, thirteen tests were ordered, twelve from Clinic B (2.6%) and one from which clinic A. Seven of eight EIAs and two of two PCRs done before the intervention were positive, all from Clinic B. Four of eight EIAs, and 0 of one PCR done after the intervention from Clinic B were positive, and the single EIA and PCR from Clinic A were each negative. The result that no patient from clinic C was screened for any risk factor, either before or after the intervention, caused problems with estimation of the multivariable logistic regression model (the Hessian matrix was not positive definite). Therefore, patients from clinic C were excluded from this analysis. In data from the remaining two clinics, inquiry about any risk factor was strongly associated with the intervention (OR= 20.5, 95%CI: 1.18-355). We also found that any inquiry was more likely in younger patients (p=0.0073) and clinic 2 patients (P=0.0011), and those treated by residents (p=0.0251). There was a significant interaction between the intervention and type of physician with residents having a greater response to the intervention than attending physicians (p=0.0052). In the analysis where inquiry about all risk factors was the dependent variable, we were unable to include an interaction

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Table 3: Changes in Reported Practice Patterns. Pre-intervention % responding yes

Post-intervention % responding yes

p-value McNemar Test

Use standard risk sheet

25.4

41.7

0.05

Ask all new patients

43.3

61.7

0.04

Offer to all at high risk

56.7

1.00

Identifying patients to test

Test all adults

0.0

Test all who request

33.3

26.7

0.29

Test all with elevated LFT

55.0

43.3

0.13

Ask about risk factors

58.3

55.0

0.69

Blood tests used to Screen Do not order tests

8.3

5.0

0.41

Anti HCV

75.0

78.3

0.53

RIBA

1.7

8.3

0.05

PCR-qualitative

21.7

13.3

0.22

PCR-quantitative

8.3

1.00

Viral Load

8.3

5.0

0.41

LFT/ALT

41.7

31.7

0.20

Let lab choose

0.0

Always send to a specialist

0.0

None

23.3

15.0

0.17

CDC guidelines

11.7

18.3

0.21

NIH Consensus Statement

13.3

10.0

0.48

MMWR recommendations

5.0

8.3

0.32

Up-to-date

70.0

76.7

0.35

Alcohol avoidance

53.3

97.4

<0.01

Acetaminophen avoidance

45.0

79.5

0.06

HAV testing/vaccination

33.3

51.4

0.48

HBV testing/vaccination

38.3

73.7

0.02

HIV testing

38.3

81.6

<0.01

VDRL/RPR

5.0

31.4

0.01

Always when HCV +

66.7

47.5

0.09

When LFTs elevated

25.7

40.0

0.44

If liver biopsy is needed

43.6

47.5

0.78

If patient requests

28.2

35.0

0.78

For end stage liver disease

51.3

40.0

0.11

No barriers

53.9

40.0

0.09

Takes too long

10.3

17.5

0.48

Insurance does not cover

10.3

15.0

0.71

Lack of insurance

18.0

35.0

0.06

Too far to travel

2.6

5.0

0.56

Specialists avoid chemical dependent patients

5.1

1.00

Patients do not want to see specialist

15.4

10.0

0.18

Materials to help diagnose/manage

Care routinely offered to HCV patients

Referral patterns in 39 physicians who made referrals in the past

Barriers to Referral

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Table 4: Patient Characteristics at Baseline. Variable Age (mean) Female sex n (%) Black race n (%) No Insurance n (%) Visit type % new n (%) % return n (%) % complete physical n (%) Previous HCV test n (%) Physician type Resident n (%) Inquire for any risk factor n (%)

Clinic A n=203 55 137(67.5) 25 (12.3) 1 (0.5)

Clinic B n=978 50 525 (54.2) 228 (23.6) 122 (12.5)

Clinic C n= 104 52 62 (60.2) 23 (23.7) 0 (0.0)

15 (7.4) 174 ( 85.7) 14 (6.9) 17 (8.4) 0 (0.0) 1 (0.5)

226 (23.1) 717 (73.3) 35 (3.6) 78 (8.0) 748 (77.6) 184 (18.8)

7 (6.7) 93 (89.4) 4 (3.9) 11 (10.6) 0 (0.0) 0 (0.0)

p-value <0.01 <0.01 <0.01 <0.01 <0.01

0.66 <0.01 <0.01

Table 5: Results of screening for risk factors and HCV testing before and after the intervention. Variable

Any Screening for risk factors Complete screening for risk factors At least one risk factor positive New HCV test ordered New HCV test done EIA+ PCR+

BEFORE INTERVENTION Clinic A Clinic B Clinic C N=203 N=978 N= 104 n (%) n (%) n (%) 1 (0.5) 185 (18.8) 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 48 (4.9) 1(0.5) 11(1.1) 0 (0.0) 18 (1.4) 0 (0.0) 13 (1.3) 0 (0.0) 5 (0.5) -

AFTER INTERVENTION Clinic A Clinic B Clinic C N=150 N=464 N=88 n (%) n (%) n (%) 8 (5.3) 198 (32.3) 0 (0.0 6 (4.0) 158 (34.1) 4 (2.6) 75 (16.2) 1 (0.7) 12(2.6) 1 (0.7) 8 (1.7) 0 (0.0) 3 (0.6) 0 (0.0) 0 (0.0) -

Table 6: Results of Multivariable Repeated Measures Generalized Estimating Equations. Variables Intervention Resident versus Attending Clinic B versus Clinic A Patient gender (male versus female) Patient age per year increase Patient race (black versus white) Visit type (return versus new) Insurance (none versus any)

Any Risk Factor ODDS RATIOS (95% CI) 20.5 (1.18-355) 1.99(1.09-3.65) 30.6(3.95-237) NS 0.98 (0.97-0.99) 0.69 (0.50-0.95 0.02 (0.01-0.03) 0.59 (0.38-0.90)

term because the low prevalence of the desired outcome in the pre-intervention period caused problems with estimation. Therefore, a model without interactions was tested. Inquiry about all risk factors was much more likely after the intervention (OR=565, 95% CI: 69-4591), and if the physician was a resident (OR=15.5, 95% CI: 4.1-59.3). No other variables were related to complete screening.

Discussion We were able to show that a multi-modality intervention improved aspects of physicians’ knowledge about HCV risk factors, screening, testing, treatment, and referral. Physicians also reported an improved confidence in managing HCV patients. The chart reviews displayed a substantial impact on physician behavior in eliciting HCV risk factors but we were unable to

All Risk Factors ODDS RATIOS (95% CI) 565 (69-4591) 15.5 (4.1-59.3) NS NS NS NS NS NS

show a significant increase in testing for HCV or diagnosis of HCV in outpatients. While the control clinic physicians did not screen any patients for risk factors either before or after the intervention, the clinic physicians exposed to the intervention increased their odds of inquiring about any risk factors by 20-fold and doing a complete risk factor evaluation by over 500-fold. Unfortunately, only two faculty physicians staffed the control clinic at the time of data collection, so the rationale for having a control group in order to strengthen inferences about the relative impact of the intervention is greatly diminished. However, it is highly unlikely that the large effects we demonstrated could be completely explained by secular trends independent of the intervention. We obtained such large odds ratios for the intervention in the complete inquiry analysis because the outcome was so rare in

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the pre-intervention period, approximately 0.08%. Also, controlling for possible confounding variables such as age, race and insurance had a great influence on the odds ratio for the intervention, which was only about 2.5 when no other variables were in the model. The impact among residents was much greater than among attending physicians. Residents were exposed to a more intensive educational experience than most attending physicians; however, all attendings in the intervention group did receive the educational materials and frequent HCV-related emails. It is likely that residents in contrast with attending physicians had less preconceived ideas regarding best practices and were more easily influenced by the intervention. Attending physicians also dealt with a higher patient census, and they may have limited time and inclination to broach lifestyle issues. It was noted that residents tended to see more new patients, whereas attending physicians saw mostly established patients. Attending physicians may incorrectly assume their established patients lack any risk factors or feel uncomfortable addressing questions that may have never been addressed in the past. The findings of this study may not be generalizable to other practices because it was done in one geographic location in clinics affiliated with a single independent academic medical center. The intervention was designed specifically for a teaching hospital setting where there were regular conferences and teaching rounds for dissemination of information. Also, we are unable to determine which aspects of the multifaceted intervention contributed the most to improving practice. If the chart reminder was a key factor, then this could easily be implemented in another practice setting. In addition, methods for physician education in non-teaching institutions could include continued medical education requirements, educational emails, and grand rounds. We must acknowledge that, although compliance with guidelines was substantially improved by the intervention, the final result was modest. Even after the intervention, only about 30% to 40% of the patients in the most compliant clinic were actually screened for all risk factors and only a minority of patients with any positive risk factor had a test for HCV. This is the first report of a multifaceted intervention that was shown to both improve physician knowledge about HCV and to demonstrate a significant change in clinical practice. It will be important to build on this success, first to improve the intervention so that the impact on patient care will be greater and to create a model that can be used in a variety of practice settings. A. M. Rebecca Daniel, MD, FACP, is Director of Clinical Research and Associate Program Director, Department of Internal Medicine, St. Joseph Mercy Hospital, Ann Arbor, Michigan.

Thomas M. Shehab, MD, is a gastroenterologist and Vice Chair, Department of Internal Medicine, Saint Joseph Mercy Hospital, Ypsilanti, Michigan. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. Dr. Moudgal reported having received support in the form of a speaker honorarium from Genentec. No other conflicts were reported.

References 1.

Alter MJ, et al. The prevalence of hepatitis C virus infection in the United States 1988 through 1994. N Engl J Med. 1999;341(8):p.556-62.

McQuillan GM, et al. Update on the seroepidemiology of human immunodeficiency virus in the United States household population: NHANES III, 1988-1994. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14(4):p.355-60.

Hepatitis C. October 24, 2007. http://www.liverfoundation.org/education/ info/hepatitisc/.

Shakil AO, et al. Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. The Hepatitis C Study Group. Ann Intern Med. 1995;123(5):p.330-7.

Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-19):p.1-39.

Management of hepatitis C. NIH Consens Statement. 1997;15(3):p.1-41.

Shehab TM, et al. Knowledge of hepatitis C screening and management by internal medicine residents: trends over 2 years. Am J Gastroenterol. 2002;97(5):p.1216-22.

Cozzolongo R, et al. Approach of primary care physicians to hepatitis C: an educational survey from a Southern Italian area. J Infect. 2005;51(5):p.396-400.

D’Souza RF, et al., Knowledge of chronic hepatitis C among East London primary care physicians following the Department of Health’s educational campaign. QJM. 2004;97(6):p.331-6.

10. Shehab TM, Sonnad SS, Lok AS. Management of hepatitis C patients by primary care physicians in the USA: results of a national survey. J Viral Hepat. 2001;8(5):p.377-83. 11. Shehab TM, et al. Identification and management of hepatitis C patients in primary care clinics. Am J Gastroenterol. 2003;98(3):p.639-44. 12. Spiegel JS, et al. Changing physician test ordering in a university hospital. An intervention of physician participation, explicit criteria, and feedback. Arch Intern Med. 1989;149(3):p.549-53. 13. Greco PJ, Eisenberg JM. Changing physicians’ practices. N Engl J Med. 1993;329(17):p.1271-3. 14. Heffner JE. Altering physician behavior to improve clinical performance. Top Health Inf Manage. 2001;22(2):p.1-9. 15. Halm EA, et al. Limited impact of a multicenter intervention to improve the quality and efficiency of pneumonia care. Chest. 2004;126(1):p.100-7. 16. Clark EC, et al. Hepatitis C identification and management by family physicians. Fam Med. 2005;37(9):p.644-9.

Bonita Singal, MD, PhD, is Associate Director for Clinical Research, Saint Joseph Mercy Health System, Ann Arbor, Michigan. Varsha Moudgal, MD, is Program Director for the Infectious Diseases Fellowship Program, Saint Joseph Mercy Hospital, Ann Arbor, Michigan.

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American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Primary Mature Cystic Teratoma of the Liver: Report of a Rare Case Brian Harris, PhD, MD, FAAR Nicole De Simone, DO, MPH

Abstract Teratomas are nonseminomatous germ cell tumors that arise from abnormal development of pluripotent and embryonal germ cells.1 They usually occur in male and female gonads and are rarely reported in extragonadal sites.2 Most findings are incidental, with imaging characteristics well described in radiological literature. To our knowledge, there have been only a few well documented cases of primary teratomas reported in the liver. Of the 26 reported, only six have occurred in adults. The majority of these cases were in female children below the age of three, mostly arising in the right lobe of the liver.1,3,4 We report a rare case of a mature cystic teratoma in the right lobe of the liver found incidentally in a 57-year-old female while undergoing CT scan of the abdomen and pelvis for abdominal pain related to a rectus hematoma. The diagnosis, pathogenesis, and the potential of malignant degeneration are discussed.

Introduction Teratomas are congenital neoplasms that contain either mature or immature tissue from all three germ cell layers. Teratomas in extragonadal locations are considered very rare occurrences, with less than 1% reported to occur in the liver.3 During fetal development germ cells follow a midline path along the urogenital ridge and descend into the pelvis as ovarian or testicular cells, hence their common midline and paramedian locations. During the first week of life, the failure of germ cells to migrate along this path and into the pelvis leads to teratomas developing in extragonadal locations.3,5 Teratomas have distinctive imag-

ing characteristics that allow for their easy identification, but histological examination is considered the current standard for definitive diagnosis and assessment of malignant potential.

Case Report A 57-year-old obese female presents to the emergency room after experiencing acute onset of left-sided abdominal pain that developed 18 hours after an enoxaparin injection. Prior to her presentation, enoxaparin injections were started for anticoagulation as a bridge for a thyroid biopsy that was taking place later that week for a suspicious nodule. Her past medical history is significant for St. Jude’s mitral valve replacement, long-term coumadin use, left nephrectomy for chronic hydronephrosis, cholecystectomy, hypertension, hypothyroidism, dyslipidemia, and diverticulosis. Her medical history was unremarkable for cancer. On physical examination she was afebrile with mild hypertension. Her abdomen was obese, soft, non-distended, with fullness and tenderness to palpation in the left abdominal wall. A working diagnosis of rectus hematoma was made, and she subsequently underwent CT scan of the abdomen and pelvis with oral and intravenous contrast to evaluate the left-sided abdominal mass. The CT scan demonstrated a 9 cm diameter hematoma in relation to the left rectus muscle. An incidental finding of a welldefined lesion within the posterior segment of the right lobe of the liver was noted to be 4.5 x 3.0cm in transverse and AP dimensions, respectively. The lesion had a thin peripheral rim.

Primary Mature Cystic Teratoma of the Liver: Report of a Rare Case

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

Fatty components were appreciated, and several areas of dense material noted to be 1000 Hounsfield units (HU) with the appearance consistent to that of teeth also noted (Figure 1, Figure 2). A diagnosis of primary dermoid in the liver was made. She was admitted to the hospital at this time for treatment of her rectus hematoma and low blood count and was discharged from the hospital in stable condition. No further workup of the liver lesion was performed at this time. Figure 1: Axial view demonstrating well-defined liver dermoid with several densities consistent to that of teeth.

Shortly thereafter she underwent robot-assisted hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraaortic lymphadenectomy. Pathology revealed lymph nodes that were negative for metastatic disease, and her final diagnosis was endometroid adenocarcinoma with focal squamous change, nuclear grade 2, FIGO 1. Approximately four months later the patient underwent follow-up CT scan of the chest, abdomen, and pelvis for evaluation of metastatic disease. Imaging revealed no metastasis and did demonstrate the same liver dermoid stable in size and appearance with no other lesions appreciated.

Discussion Teratomas are congenital anomalies that arise from abnormal development of pluripotent cells of embryonic rests and may contain virtually any tissue type that is not typically native to the organ in which they are found.6 Dermoid cysts and mature teratomas are synonymous, and their names are commonly used interchangeably. Dermoid cysts are considered a form of mature teratomas that predominantly contain tissue of ectodermal derivation.1,3 They are characteristically uniloculated cysts lined by skin, and they may contain sebaceous material, hair, teeth, calcifications, or cartilage.1

Figure 2: Coronal reformatted image demonstrating fatty components and several teeth.

A few months later she presented to her OB/GYN doctor with post-menopausal bleeding that prompted a biopsy, which revealed endometroid adenocarcinoma with squamous metaplasia.

Dermoid cysts most commonly occur in the ovary or testes with extragonadal sites reported to occur in order of decreasing frequency from the anterior mediastinum, retroperitenoum, sacrococcygeal region, central nervous system, and liver.1 Three proposed theories exist for the causes of extragonadal teratomas. The first theory, which is most commonly cited in the literature, suggests that primary dermoids originate from displaced germ cells that arrested along the migration path from the allantois hingut to the gonads during the first week of life. The second theory suggests that they develop from supernumerary ovaries. Lastly, they are theorized to be secondary to auto-implantation of an ovarian dermoid and reimplantation of it into an extragonadal site.7 There are four histological variants of teratomas that are described: mature teratoma, immature teratoma, teratoma with malignant transformation, and monodermal teratoma.1,2 Mature teratomas are usually cystic and benign but have the potential to undergo malignant transformation. This has been reported in the literature to occur in 1-2% of cases, usually in postmenopausal women during the sixth and seventh decade of life with similar imaging appearances to that of a benign mature cystic teratoma. Almost any component may become malignant, but squamous cell carcinoma accounts for 80% of cases. Complications such as cyst rupture and malignant degeneration can cause leakage of liquefied sebaceous contents into the peritoneum and further complicate the patient’s course and prognosis.1,2,8,9 Immature teratomas are much less common and usually occur during the first two decades of life. Histologically they have the presence of immature tissue. At initial presentation they are generally larger at 14-25 cm versus that of mature teratomas, which usually average about 7 cm. Immature teratomas can undergo what is known as “retroconversion” in which the tissue

Primary Mature Cystic Teratoma of the Liver: Report of a Rare Case

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

can appear more mature on imaging and remain stable for long periods of time.9 Morphologically, mature teratomas are cystic, whereas immature teratomas are predominately solid with small foci of fat.9 The majority of mature cystic teratomas are asymptomatic unless obstructive symptoms develop and, hence, are usually found incidentally on CT scan. Findings of a mass containing fat, fluid, and calcifications are virtually diagnostic of a teratoma.9,10 Fat is reported in 93% of cases, with teeth or calcifications reported in 56% of cases.9 CT scans give more specific information on fat, proteinaceous fluid, and calcifications by using HU.11 CT scan readily identifies fat as hypodense with HU of -60 to -100, demonstrating a density similar to subcutaneous fat, and calcifications appear as markedly hyperattenuating foci.1,3,5 Further imaging with MRI does allow for improved soft tissue identification and can be useful for diagnosing invasion of blood vessels, malignant potential, and the potential for resectability.2,11 Mature cystic teratomas grow slowly at an average rate of 1.8 mm each year, prompting some to advocate non-surgical management of smaller, less than 6.0 cm, tumors.9 However, definitive diagnosis is achieved by histological examination only, and surgical resection is considered the mainstay of treatment, because the presence of immature tissue affects the prognosis of the patient adversely.2,5,6,12 In conclusion, the case we describe here represents a rare case of primary mature teratoma in the right lobe of the liver in an adult. Although they are typically benign, malignant transformation has been known to occur and changes the patient’s prognosis drastically. Our patient’s repeat imaging showed the teratoma remained stable; however, the question remains as to whether this is truly a benign teratoma or somehow related to her diagnosis of endometrial cancer. Recommendations for surgical excision of the teratoma in this patient should be discussed. Although CT scans allow for the diagnosis of teratoma prior to surgery, further interventions to obtain histopathology should be considered. Brian W. Harris, PhD, MD, FAAP, Principal Investigator, is Director of Radiology Department, PinnacleHealth Hospital System, Community General Hospital, Harrisburg, Pennsylvania.

Nicole DeSimone, DO, MPH, Assistant Principal Investigator, is General Surgery Resident, PinnacleHealth Hospital System, Community General Hospital, Harrisburg, Pennsylvania. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The authors have stated that no such relationships exist. ®

References 1.

Certo M, Franca M, Gomes M, et al. Liver Teratoma. Acta Gastroenterol Belg. 2008;71(2):275-279.

Souftas V, Polychrondis A, Giatromanolaki A, et al. Dermoid Cyst in the Hepatoduodenal Ligament: Report of a Case. Surg Today. 2008;38:959-961.

Rahmat K, Vijayananthan A, Abdullah BJJ, et al. Benign teratoma of the liver: A Rare Cause of Cholangitis. Biomed Imaging Interv J. 2006;2(3):20.

Winter TC, Freeny P. Hepatic Teratoma in an Adult. Case Report with a Review of the Literature. J Clin Gastroenterol. 1993;17(4):308-310.

Martin L, Papadatos D, Michaud C, et al. Best Cases from the AFIP: Liver Teratoma. RadioGraphics. 2004;24(5):1467-1471.

Fernandez-Cebrian J, Carda P, Morales V, et al. Dermoid Cyst of the Pancreas: A Rare Cystic Neoplasm. Hepato-Gastroenterology. 1998;45:1874-1876.

Khoo C, Chua I, Siow A, et al. Parasitic Dermoid Cyst of the Pouch of Douglas: A Case Report. The Journal of Minimally Invasive Gynecology. 2008;15:761-763.

Brustmann, H. Intestinal Metastases in a Squamous Cell Carcinoma Arising in Mature Cystic Teratoma of the Ovary: A Case Report. Annals of Diagnostic Pathology. 2006;10:374-375.

Outwater E, Siegelman E, Hunt. Ovarian Teratomas: Tumor Types and Imaging Characteristics. RadioGraphics. 2001;21:475-490.

10. Prasad S, Wang H, Rosas H, et al. Fat-containing Lesions of the Liver: Radiologic-Pathologic Correlation. RadioGraphics. 2005;25:321-331. 11. Taori K, Rathod J, Deshmukh A, et al. Primary Extragonadal Retroperitoneal Teratoma in an Adult. The British Journal of Radiology. 2006;79:120-122. 12. Kommoss F, Emond J, Hast J, et al. Ruptured Mature Cystic Teratoma of the Ovary with Recurrence in the Liver and Colon 17 Years Later: A Case Report. Journal of Reproductive Medicine. 1990;35:827-831.

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Primary Mature Cystic Teratoma of the Liver: Report of a Rare Case

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sounding board

NOT Flat Stanley’s Big Vacation Dr. Ed Thornton on Foreign Medical Work Martin E. Thornton, DO

OK, Flat Stanley was just to get your attention for the real story. Six months ago I was working my usual day in/day out life and a phone call changed my plans for a while. The Tanzanian government had worked to start a clinic in Kigombe, Tanzania. If you Google Earth Kigombe, you will see that it is conveniently in the northern part of Tanzania next to the city of Tanga and close to the border of Kenya. If that doesn’t work, you can put one leg on Mombasa, Kenya, and play twister to get the other leg on Dar es Salaam, Tanzania. Then, put your hand right in between your legs, and there in the middle is Tanga. It is a coastal area where many islands (the most famous of which is Zanzibar) are located and the people basically fish for a living. They encounter many difficult diseases that love the eastern coast of Africa, such as malaria, typhoid, dengue, Loa Loa, Wucheria Bancroft, HIV/AIDS, and so on. There are more than half a million people in the Kigombe region alone, and they are affectionately referred to as the “Fisherfolks.” After five years trying and failing to establish a hospital in this area, the government of Tanzania decided to ask for international help. As some of you know, I travel from time to time, and I usually have my little black doctor’s bag in tow. The phone call came from the International Hospital Association rather by surprise, asking if I might be interested in working with the fishing community of Kigombe. Since I love seafood, I volunteered right away and, after some discussion my wife, who is a nurse, also agreed that this was a real opportunity to make a difference someplace and eat some nice seafood. When I started making plans, it was clear that every hospital needed an administrator so I enquired about who such person would be. Oddly, my two dear friends from Mwanza, Tanzania, near Lake Victoria had decided to go there and work with a team of employees to start this project and actually see patients.

Dr. Thornton

There was, in the background, a lovely British woman who had lived on the shores of the Indian Ocean with her husband in Kigombe. It was in their plan to retire there, and so they needed a home. There was no electricity in Kigombe so this was a bit of a problem. But, you know those British and how clever they are. Soon after the house was built, they installed a solar panel. Just one solar panel did they install. There were no solar batteries in Kigombe so they improvised and used a simple 12 volt car battery. Only one such battery was used for the entire compound. So they made a solar oven, which boiled water for consumption, and cooked food that was excellent, such as a mush called Oogali (its name obviously from the first bite (which causes one to say, “Ooh, gawli, that is nasty.”) and seafood. However, as fate sometimes intervenes, her husband died, and she was left alone with the solar oven and a car battery. Her husband’s illness would have been innocuous in nearly any other place with a clinic, but since none was nearby, he passed on. This caring British lady approached the Tanzanian authorities about donating her compound to be used as a hospital, and so it was that a simple daily occurrence like death created an opportunity.

NOT Flat Stanley’s Big Vacation . . .

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

sounding board ing, learning from, and working with for a few weeks looked like. Suddenly, it dawned on me that they all lived in the same compound and shared living spaces that were for common purposes, like eating and evening visits. I could live with that, I thought. It was late, so we worked into the night getting out medicine, equipment, and mosquito repellant.

Solar Oven

Enter the family who lived there and were missionaries for 25 years in Mwanza, Tanzania. The husband is an accountant by education. His wife is a nurse by training. What a couple! Every hospital must start with administration. Since the Tanzanians had failed, and other NGOs could not come up with personnel and equipment, the project floundered (Fisherfolks know flounder!). It floundered without ever opening or seeing a patient until my friends, the accountant and the nurse came into the picture. The only thing they needed was doctors, some nurses, and, of course, they needed medication and equipment to make this once-British home into a hospital. That should be easy enough. My wife and I have known the family from Mwanza, and we have worked with them in many places in East Africa. We decided that opening this hospital/clinic was a serious undertaking worth whatever we could also provide in manpower, encouragement, and supplies. I wrote a few grants, bought a few medications, convinced my dear doctor friend in Pocatello, Idaho, that this would be a rewarding and rich experience, and so, off we went to help do a good deed. We arrived in Dar es Salaam after 30 hours of travel via Amsterdam. When we arrived, it was clear that the medication and people would overwhelm the Land cruiser, so my wife and I with no hesitation jettisoned the luggage and rented a small Cessna (with the pilot since I can’t fly), and we were off. The plane took us to Zanzibar, then Pemba Island, and finally Tanga where we met the house and clinic with one battery and the solar oven. My first thought was that shaving would draw too much electricity so I quickly decided that the beard was going to grow. Then I noticed there were people already living in the house. They were cooking and cleaning. I met the house cook and her son. Then the clinic nurses said hello, followed by a warm reception from my great friend and translator with whom I’ve worked many hours in Mwanza. Next a young Tanzanian doctor came in to see what the American doctor he would be teach-

In the night I heard a roaring noise that ebbed and flowed like the most accomplished of loud snoring men. Through the night it sounded further and further away. It was a lullaby for sleep and even soothed my swollen legs. The next morning it was barely audible, and it was then that I knew the Indian Ocean was in our back yard and the tide was out nearly a mile, making the waves silent. I only walked the beach once, but it was beautiful. The work started, and clinic on the first day was fun. The sick were really sick. I saw children, adults, and old men and women who had malaria and typhoid. The skin conditions were so challenging that even in my imagination I could hear the whispers of the dermatopathologist saying, “It’s a complex skin condition, stupid. You need a biopsy!” One little six-month-old girl really caught my attention that day. She had Norwegian type scabies and had scratched the surface of her skin until she was covered in impetigonous lesions from head to toe. The suffering from just a scabies infestation was a fast reminder of how serious and chronic most of my patients would be. The next child had malaria, confirmed by thick and thin smears so that I could see the parasite under an ancient microscope. Do you remember “oil immersion”? What a throw back!

Norwegian Scabies

Then there was the man with a scrotum the size of a wheel barrow from elephantiasis. The book says treat it with Ivermectin now and every six months for a year and a half. Where do they sell Ivermectin in Tanga? In my mind I was a bit jealous of a man packing a bulge in his pants the size of Rhode Island. After seeing “Rhode Island” I felt like crying. For six years he had suffered with this disease, and now the great American doctor could help? The quest for Ivermectin became as intense as the quest for the Holy Grail and was as complicated, humorous, and convoluted as a Monty Python movie.

NOT Flat Stanley’s Big Vacation . . .

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

sounding board The days to come soon did – get up at six, eat oatmeal or fruit, then work, then work a bit more, then lunch, work, supper and collapse for sleep, and wait for the sound of the snoring ocean. One evening I awoke abruptly wondering if I was having a Mefloquine dream, or did that large creature staring at me from my bed rail really run by me with fearless intention. It was not a Mefloquine nightmare, only a very large rat. The safari began and the hunt was on. I used traps with my best peanut butter and bacon enticements. Tripped and bare, the traps were abandoned for something every hunter on safari needs. I imagined using a shotgun, but only to come to reality that it would end up like a Three Stooges episode. So I turned to poison in frustration (and there are no shotguns in Tanzania unless they come with a soldier!) So, why did we go? Helping to open a clinic was a challenge. Knowing that we could accomplish something others had failed to do was a noble goal. During the week, it became clear. The real reason was the benefit that comes with meeting and caring for people who are poor and have little knowledge or access to any health care. These “Fisherfolks” were gentle and kind Muslims who accepted us and shared everything they had (including scabies – my first stop at home was the Permethrin 5% store). We were invited into their homes and often they were apportioned with so little that subsistence took on a whole new point of view. They shared whatever fish they had to eat, and squid was so abundant that I don’t ever want to think about eating it again. They were as clean as they could be. They loved their children and cared for them, often without eating anything because there was only one serving.

Neighbor’s Boat

At the end of the day, when it had all been said and done, living with the doctors, nurses, cooks, and administrators under one roof and with one car battery and a solar oven was a bit of a challenge emotionally and physically. During those days, I would often think about ham and eggs, a hot shower, or a chocolate cake. Everyone worked hard and without everyone nothing would have happened. Every person’s skill and gift was needed every day. I realized that I was living in a village

and that every person mattered and depended on everyone else. Who boiled the water in the daytime? I don’t know, but that was as important as who was working in the clinic. An interesting example and bright spot was how my wife took a few vegetables, tomatoes, and spices to cook for 15 or more people every evening without a grocery store or a Whataburger in driving distance. The fruit for dessert was mango, papaya, watermelon, and the old standby banana taken from the local tree. My wife is a nurse by trade, but on this trip we needed a cook who could make something out of little or nothing, so she became a gourmet chef in Kigombe. No one complained, and no one got sick. Many actually thought it was the best food they had eaten in a very long time, since they did not have to cook it. Life if full of illness, kind acts, serendipity, sharing, and living in a place where real community is present and tangible as every breath taken there in the warm humid air. I left feeling very tired after my time of work. The young Dr. Dickla Jackson (what kind of name is “Jackson” in Tanzania?) and I learned a great deal from each other. He emails me with his tough cases and dreams that we will come again someday to Kigombe. Even with scabies, I somehow think there will be another trip to that place, just so I can see how much was done to start a clinic and then see the vision of a clinic growing into a really important community center. Now, the story isn’t over yet. My wife and I had our silver 25th wedding anniversary while we were there. It’s hard to celebrate with scabies and a whole house full of people so we flew back to Zanzibar for the time to reflect on work and lives lived well. The hot shower was abused that first night, and every moment on the island was met with contentment and rest. It was a small reward for being allowed just to help in the vision of the International Hospital Association, and the Bentley family, on a mission to change the world by bringing health and healing to a place that has none! Martin E. Thornton, DO, is board certified in emergency medicine and is the chairman of the American Board of Disaster Medicine. He is Chief Medical Officer, Texas Disaster Medicine Assistance Teams, and an emergency physician at Emerus Hospital. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The author has stated that no such relationships exist.

NOT Flat Stanley’s Big Vacation . . .

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

The Role of Physician Experience in Pelvic Examination Accuracy Daniel M. Avery, Jr., MD, FAASS Jason M. Parton, MA, MS John C. Higginbotham, PhD, MPH

Objective

Introduction

The primary goal of this study was to determine the role of physician experience in clinical pelvic examination accuracy.

The clinical pelvic examination is an integral component of the examination of female patients to assess the external genitalia, vagina, cervix, uterus and adnexa.1,2,3,4 These exams screen the lower genital tract for infection, dysplasia, cancer, pelvic relaxation, pelvic floor abnormalities, abnormal bleeding, incontinence, tenderness, dyspareunia, foreign bodies, sexual assault, trauma, vaginismus as well as uterine and adnexal abnormalities.3,5,6,7,8,9 Women who present for medical care with pelvic complaints usually receive a clinical pelvic examination.10

Methods A retrospective chart review of 507 women aged 15 to 70 years of age who had received a pelvic ultrasound examination between November 1, 2008, and October 30, 2009, at the University Medical Center OB/GYN Clinic was undertaken. Of this number, 356 had concurrently received a clinical pelvic examination.

Results Approximately 61% of abnormal clinical pelvic examinations were confirmed by pelvic ultrasound examination, while 92% of normal clinical pelvic examinations were confirmed by pelvic ultrasound examination. Physicians with less experience commonly diagnosed normal clinical pelvic examinations. Experienced physicians more frequently diagnosed abnormal clinical pelvic examinations. Both examinations were concordant 75% of the time.

Conclusions Our results indicate that inexperienced physicians commonly diagnose normal pelvic examinations, while experienced physicians are more likely to diagnose abnormal clinical pelvic examinations that are confirmed by ultrasound examination. Examinations were concordant 75% of the time.

In the study by Padilla et al.4, the sensitivity for pelvic examination was lowest for medical students and highest for attending gynecologists who had the best consistent performance.4,11 Years of experience improved diagnostic ability but not adnexal assessment.4,11 The diagnostic value and efficacy of clinical pelvic examination has been questioned because of the significant limitations of bi-manual examination of the adnexa.4,6 Detection of ovarian cancer has also been shown not to be reliable.4,6 Some have reported that masses as large as 5 centimeters in diameter are frequently missed at pelvic examination.6 A mobile ovarian mass (i.e., one that is not fixed in the pelvis) can slip between the examining hands at pelvic examination and thus escape detection in even the most experienced hands. Consequently, the routine pelvic bimanual examination may not meet the standards of good evidence-based medicine.4 A negative pelvic examination may even falsely reassure the patient and physician that there is no ovarian cancer present.3 Other documented limiting factors of pelvic examination relate to patient size and patient cooperation.12

The Role of Physician Experience in Pelvic Examination Accuracy

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

A study by Padilla et al. compared pelvic examination under anesthesia with diagnostic laparoscopy or laparotomy and found that even under the best circumstances, bimanual examination has significant limitations for the evaluation of the adnexa.4,6 Other factors that have been found in the literature to compromise assessment of the uterus and adnexal masses relate to patient’s obesity, uterine size, abdominal scars, atrophic changes, pelvic organ prolapse, uterine mobility, fixation in the pelvis, an intact hymen, lack of sexual activity, position during the examination as well as infrequent examination, insufficient training of the examiner, the examiner’s gender, integrity during the examination, and the patient’s level of trust in the examiner.6,8,9,10,13 Compromised pelvic examinations are also associated with anxiety and pain.13 Pelvic examinations have been shown to be more accurate in evaluating the uterus rather than the adnexa and correlate well with ultrasound when uterine fibroids are present.4,7,14

Materials and Methods This study was a retrospective chart review of pelvic ultrasound examinations in patients who had previously undergone clinical pelvic examinations. These patients had been seen at the University Medical Center at the University of Alabama School of Medicine in Tuscaloosa, Alabama, between November 1, 2008, and October 30, 2009. The study was approved by the Institutional Review Board of the University of Alabama. For the purposes of this study a clinical pelvic examination was considered normal if the uterus was less than eight weeks gestation size or less than 8 centimeters in length and there were no adnexal masses or cysts 4 centimeters or greater; anything larger than these dimensions was considered abnormal. A pelvic ultrasound examination was considered normal if the uterus was less than 8 centimeters in length and there were no adnexal masses or cysts 4 centimeters or greater; anything larger than these dimensions was considered abnormal. The uterus may be enlarged, pregnant, or contain a mass, such as a fibroid. The adnexa may contain an ovarian cyst or mass 4 centimeters or greater. The clinical records of the examinations and ultrasounds were evaluated by the principal investigator, whose clinical examinations and pelvic ultrasounds had been excluded from the study. Pelvic ultrasound examinations were performed by a single, experienced ultrasound technician with 30 years experience on a General Electric Voluson 730 PRO Ultrasound. Results of the ultrasounds were interpreted by ultrasound trained OB/GYN physicians and scanned into the electronic medical record of the patients. Clinical pelvic examinations were performed by OB/GYN attending physicians at the University of Alabama School of Medicine in Tuscaloosa who were all either board certified or board eligible in OB/GYN. Years of experience performing pelvic examinations ranged from six to thirty years. Clinical pelvic examinations were indicated by a pelvic or gynecologic complaint or initial pelvic examination as part of an initial obstetric examination for pregnancy. Pelvic examinations were performed by an initial speculum examination followed by a

gloved bimanual pelvic examination. Results were recorded in the patient’s chart in an electronic medical record. Analysis was conducted on a sample of 356 patients using SAS software version 9.1.3. The sample consisted of measurements of physician years of experience, results from clinical pelvic examinations and pelvic ultrasound examinations, weights and ages of the patients, and a created variable examining continuity between the exams. This study investigated the frequency of these variables along with univariate inferential comparisons.

Results The retrospective study consisted of 507 patients aged 15 to 70 years of age who had received a pelvic ultrasound examination between November 1, 2008, and October 30, 2009, at the University Medical Center OB/GYN Clinic at The University of Alabama School of Medicine, Tuscaloosa Campus. Seventy percent of these women (356) had previously undergone a clinical pelvic examination. Results indicate an abnormal frequency for pelvic ultrasound exams at 50.69%, compared to 37.35% for a clinical bimanual pelvic exam. Thirty percent of patients did not receive a clinical pelvic exam. The two examinations were concordant 75% of the time. The sample of 507 patients with ultrasound examinations was studied in relation to patients who also received a clinical pelvic exam. The resulting number of patients receiving both an ultrasound exam and a clinical exam was 356. To understand why, a rate comparison was conducted between physicians who performed a pelvic ultrasound exam and those who also performed a clinical pelvic exam. An analysis showed a rate ratio of 1.42 (1.35, 1.51); 95% indicating physicians are 42% more likely to conduct only an ultrasound exam rather than both an ultrasound and a clinical exam. Results are shown in Table 1. Table 1: Sample Characteristics.

Ultrasound Exam

Clinical Pelvic Exam

Consistency of Exams

Frequency

Percent

Abnormal

257

50.69%

Normal

250

49.31%

Abnormal

133

26.23%

Normal

223

43.98%

Not Done

151

29.78%

Concordant

267

75.00%

Discordant

25.00%

Another interest of this study was to inspect if there is a correlation in the number of years a physician has been practicing and whether or not he or she performs a clinical pelvic exam. The analysis shows that the proportion of pelvic exams conducted differs significantly by the number of years of physician experience, χ² (2, N = 507) = 6.56, p < 0.05. Results indicate catego-

The Role of Physician Experience in Pelvic Examination Accuracy

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

ries 0-10 and 30+ years of experience perform the most pelvic examinations more than 70% of the time, while the 20-29 category perform pelvic exams only 58.11% of the time. Results are shown in Table 2. Since this study has, in essence, two samples (patients who received an ultrasound exam and those who received both an ul-

Table 2: Crosstab and Chi-Square Analysis

trasound exam and a clinical pelvic exam), a measure of linkage was created to inspect the continuity of the two exams. This inspection of concordance between a clinical pelvic exam and an ultrasound exam was conducted using a cross tabulation with a Pearson Chi-square. The analysis reveals a statistical difference between the proportions of ultrasound and clinical pelvic

Table 2: Crosstab and Chi-Square Analysis.

Conducted both ultrasound and clinical exam, n = 356 Clinical Exam

Ultrasound Exam

Abnormal Normal

Abnormal

Normal

Statistic

Probability

120 (90.23%) 13 (34.36%)

76 (34.08%) 147 (65.92%)

χ² = 106.13

< 0.0001

Exams by years of physician experience, n = 507 Years of Physician Experience

Ultrasound Exam

Abnormal Normal

Abnormal Clinical Exam

Normal Not Done

Performed Pelvic Exam

Consistency of Exams

Yes No

Concordant Discordant

0 - 10

20 - 29

30 +

Statistic

Probability

85 (46.45%) 98 (53.55%)

38 (51.35%) 36 (48.65%)

134 (53.60%) 116 (46.40%)

χ² = 2.18

27 (14.75%) 102 (55.74%) 54 (29.51%)

13 (17.57%) 30 (40.54%) 31 (41.89%)

93 (37.20%) 91 (36.40%) 66 (26.40%)

χ² = 36.60

< 0.0001

129 (70.49%) 54 (29.51%)

43 (58.11%) 31 (41.89%)

184 (73.60%) 66 (26.40%)

χ² = 6.56

0.0376

94 (72.87%) 35 (27.13%)

25 (58.14%) 18 (41.86%)

148 (80.43%) 36 (19.57%)

χ² = 9.73

0.0077

= Not significant at α > 0.05) (NS The Role of Physician Experience in Pelvic Examination Accuracy

American Journal of Clinical Medicine® • Winter 2011 • Volume Eight, Number One

exam outcomes compared to ultrasound pelvic exam outcomes, χ² (1, N = 356) = 106.13, p < 0.001. Patients diagnosed as abnormal with an ultrasound examination were diagnosed as normal with a clinical examination 34% of the time. As a total comparison, diagnosis from a clinical examination was normal 62.64% of the time while an ultrasound exam diagnosis was normal only 44.94% of the time. This result demonstrates that ultrasound pelvic exams show abnormalities 17.70% more than clinical pelvic exams, and, of those clinical pelvic exams that provided a normal diagnosis, 76 were diagnosed as abnormal by ultrasound exam. Additional methods were performed to further examine the concordance of the ultrasound and bimanual pelvic exams by the years of physician experience. Ultrasound and clinical exams with the same outcomes were designated as concordant, while differing results were deemed discordant. Results of cross tabulation and Pearson Chi-Square show a statistically significant difference in proportions of concordant and discordant outcomes as related to a physician’s years of experience, χ² (2, N = 356) = 9.73, p < 0.05, with the experience category 30+ resulting in the most concordant outcome (80.43%). The years-of-experience group with the most discordant outcomes is 20-29 (41.86%).

Discussion This study confirms the accuracy of pelvic ultrasound examinations compared to clinical bimanual pelvic examinations. An ultrasound examination has been shown to have improved accuracy over pelvic bimanual examination.11,13 Transvaginal ultrasonography has been shown to produce an accurate assessment of the uterus and adnexa.10,11,14 Transvaginal ultrasonography is superior to vaginal bimanual examination in diagnosing gynecologic pathology, especially ovarian masses.15 This study raises the question of the reliability of the pelvic exam for evaluating adnexal masses especially ovarian cancer.6 When an ovary is enlarged by pelvic examination, a transvaginal ultrasound should be performed.16 Physicians with the least experience in this study were good at diagnosing normal pelvic examinations confirmed by sonar. When pelvic sonar was normal, there was a 92% chance that any physician would confirm it clinically. However, more experienced physicians were more accurate at diagnosing abnormal pelvic exams. In the study by Padilla et al.,4 the sensitivity for pelvic examination was lowest for medical students and best for attending gynecologists, who had the best consistent performance.4,11 Years of experience improved diagnostic ability but not adnexal assessment.4,11 Pelvic examination may be a good screening tool as long as both the examiner and the patient appreciate the limitations.6 A negative pelvic examination may even falsely reassure the patient that there is no evidence of ovarian cancer when that is indeed not the case.7 Daniel M. Avery, Jr., MD, FAASS, is Professor and Chairman, OB/GYN Department at The University of Alabama School of Medicine.

Jason M. Parton, MA, MS, is Epidemiologist and Project Director, Rural Health Institute for Research and Translational Science, College of Community Health Sciences, University of Alabama School of Medicine, Tuscaloosa. John C. Higginbotham, PhD, MPH, is Associate Dean, Research and Health Policy; Director, Institute for Rural Health Research; Professor, Chair Community and Rural Medicine. Potential Financial Conflicts of Interest: By AJCM policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The author has stated that no such relationships exist. ®

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Bell WB. The Principles of Gynaecology. Longman, Green and Co. London. 1910. 113.

Sims JM. Clinical Notes on Uterine Surgery. Robert Hardwicke. Piccadilly. 1866. 6-25, 261.

American College of Obstetrics and Gynecology. Routine Pelvic Examination and Cervical Cytology Screening. ACOG Committee Opinion. Obstet Gynecol. 2009;113(5):1190-3.

Padilla LA, Radosevich DM, Milad MP. Limitations of the Pelvic Examination for Evaluation of the Female Pelvic Organs. International Journal of Gynecology and Obstetrics. 2005;88:84-8.

Stewart RA, Thistlethwaite J, Evans R. Pelvic Examination of Asymptomatic Women. Australian Family Physician. 2008;37(6):493-6.

Padilla LA, Radosevich DM, Milad MP. Accuracy of the Pelvic Examination in Detecting Adnexal Masses. Obstet Gynecol. 2000;96(4):593-8.

Wakley G. NLH Primary Care Answering Service (Website Review). J Fam Plann Reprod Health Care. 2005;31(4):337.

Blake DR, Fletcher K, Joshi N, Emans SJ. Identification of Symptoms that Indicate that a Pelvic Examination is Necessary to Exclude PID in Adolescent Women. J Pediatr Adolesc Gynecol. 2003;16:25-30.

Desai AK, Jaiyesimi RAK. A Survey of the Value of Routine Intimate Examination and Related Practices in Subfertile Couples. Journal of Obstetrics and Gynecology. 2007;27(8):840-44.

10. Condous G, Van Calster B, Van Huffel S, Lam A. What is the value of Preoperative Bimanual Pelvic Examination in Women Undergoing Laparoscopic Total hysterectomy? Journal of Minimally Invasive Gynecology. 2007;14(3):334-8. 11. Carter JC, Fowler J, Carson L, Carlson J, Twiggs LB. How Accurate is the Pelvic Examination as Compared to Vaginal Sonography? J Reprod Med. 1994;39(1):32-4. 12. Russell DJ. The Female Pelvic Mass. Office Gynecology. 1995;79(6):14811493. 13. Tayal VS, Crean CA, Norton J, Schulz CJ, Bacalis KN, Bliss S. Prospective Comparative Trial of Endovaginal Sonographic Bimanual Examination Versus Traditional Digital Bimanual Examination in Nonpregnant Women with Lower Abdominal pain with Regard to Body Mass Index Classification. J Ultrasound Med. 2008;27(8):1171-7. 14. Cantuaria GHC, Angioli R, Frost L, Duncan R, Penalaver MA. Comparison of Bimanual Examination with Ultrasound Examination Before Hysterectomy for Uterine Leiomyoma. Obstet Gynecol. 1998;92(1):109-12. 15. Frederick JL, Paulson RJ, Sauer MV. Routine Use of vaginal Ultrasonography in the Preoperative Evaluation of Gynecologic Patients. J Reprod Med. 1991;36(11):779-82. 16. Rulin MC, Preston AL. Adnexal Masses in Postmenopausal Women. Obstet Gynecol. 1987;70(4):578-81.

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