Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy has been in the limelight in 2014—particularly morcellation performed in an “open” fashion (without use of a protective bag). Concerns about the dispersion of tissue throughout the peritoneal cavity—including the risk of disseminating tissue from leiomyosarcoma, a rare but deadly cancer—have drawn statements from the American College of Obstetricians and Gynecologists (ACOG), the AAGL, the US Food and Drug Administration (FDA), and others, cautioning against the use of open power morcellation in women with a known or suspected malignancy.

In July 2014, the FDA convened a two-day hearing of the Obstetrics and Gynecology Devices Panel (one of the panels in its Medical Devices Advisory Committee) to consider whether power morcellation should remain an option and, if so, what restrictions or labeling might be recommended.

In advance of the FDA hearing, OBG Management invited two experts in women’s health to explore the options more deeply and address the future of minimally invasive surgery (MIS): Ray A. Wertheim, MD, Director of the AAGL Center of Excellence Minimally Invasive Gynecology Program at Inova Fair Oaks Hospital in Fairfax, Virginia, and Harry Reich, MD, widely known as the first surgeon to perform laparoscopic hysterectomy, among other achievements. Both Dr. Wertheim and Dr. Reich were members of the AAGL Tissue Extraction Task Force.

In this Q&A, Dr. Wertheim and Dr. Reich discuss:

• options for tissue extraction going forward
• the importance of continuing to offer minimally invasive surgical approaches
• the need to educate surgeons about the safest approaches to tissue extraction.

Both surgeons believe that power morcellation should remain an option for selected cases, although neither performs the technique himself. Both surgeons also believe that minimally invasive approaches to hysterectomy and myomectomy are here to stay and should continue to be used whenever possible.

AAGL convened an impartial expert panel
OBG Management: Dr. Wertheim, could you tell us a little about the AAGL position statement on the use of power morcellation for uterine tissue extraction at hysterectomy or myomectomy, since you were on the task force that researched and wrote it?¹

Dr. Wertheim: AAGL convened its task force to conduct a critical appraisal of the existing evidence related to the practice of uterine extraction in the setting of hysterectomy and myomectomy. Areas in need of further investigation also were identified.

The task force consisted of experts who had no conflicts, were not allowed to discuss or review findings with anyone, and were not reimbursed for their time. Our review is the most complete report to date, more comprehensive than the current reports from the FDA, ACOG, the Society of Gynecologic Oncology (SGO), and the American Urogynecologic Society (AUGS).

Interestingly, AAGL, ACOG, SGO, and AUGS all reached the same conclusion: All existing methods of tissue extraction have benefits and risks that must be balanced.

OBG Management: How did the AAGL Task Force assess the evidence?

Dr. Wertheim: The quality of evidence and strength of recommendations were assessed using US Preventive Services Task Force guidelines. There are very few good data on the issue of power morcellation for uterine tissue extraction, especially in regard to leiomyosarcoma. One needs to be careful making recommendations without good data.

Related article: First large study on risk of cancer spread using power morcellation. Janelle Yates (News for your Practice; August 2014)

At this time, we do not believe there is a single method of tissue extraction that can protect all patients. Therefore, all current methods should remain available. We believe that an understanding of the issues will allow surgeons, hospitals, and patients to make the appropriate informed choices regarding tissue extraction for individual patients undergoing uterine surgery.

How to manage tissue extraction going forward
OBG Management: Regardless of the FDA’s final decision, what should the gynecologic specialty be doing to avoid disseminating uterine tissue in the peritoneal cavity, particularly leiomyosarcoma?

Dr. Wertheim: MIS is a wonderful advancement in women’s health care. All surgical specialties are moving toward MIS. Our challenge is to perform it as safely as possible, given the data and instrumentation available.

In regard to leiomyosarcoma, because we lack the ability to accurately make the diagnosis preoperatively, we’ve identified risk factors that should be taken into consideration. They include advanced age, a history of radiation or tamoxifen use, black race, hereditary leiomyomatosis, renal cell carcinoma syndrome, and survival of childhood retinoblastoma.

At this time, we have specimen-retrieval bags that can be used with power morcellation. However, it takes skill to be able to place a large specimen inside a bag without injuring surrounding organs due to limited visibility.

Education, at the hospital and national level, is in the works
OBG Management: How should we go about educating surgeons about MIS alternatives to open power morcellation?

Dr. Wertheim: In my hospital, we are mentoring surgeons to help them gain the new skills needed. In addition, I plan to give a grand rounds presentation on tissue extraction for hospitals in northern Virginia and also would like to offer a course in the near future. I’m also hoping that we’ll be able to offer courses around the country before the annual AAGL meeting this November.

At the annual AAGL meeting, the subject will be discussed at length, with an emphasis on identifying risk factors and conducting appropriate preoperative testing, with workshops likely to teach the skills needed to perform these surgeries as safely as possible.

Why a return to reliance on laparotomy would be unwise
OBG Management: Given all the concerns expressed recently about open power morcellation, do you think some surgeons will revert to abdominal hysterectomy rather than rely on MIS? Would such a move be safer than power morcellation?

Dr. Wertheim: That would be a disaster for women. Very reliable data have shown that MIS is safer than open surgery, with much quicker recovery. Almost all of my patients are discharged within 3 hours after surgery, and most no longer require pain medications other than nonsteroidal anti-inflammatory drugs by postoperative day 2. They’re usually back to work within 2 weeks.

We have worked long and hard to develop skills and instrumentation required to perform MIS safely—but nothing replaces good judgment. In some cases, laparotomy or conversion to a laparotomy may be indicated.

New instrumentation is needed and is being developed. In the meantime, my personal bias is to rule out risk factors for malignancy and continue to morcellate with a scalpel, preferably inside a bag. After all, we know that with open power morcellation, fragments and cells are usually left behind regardless of inspection and irrigation. These fragments may cause leiomyomatosis, endometriosis, bowel obstruction, sepsis, and possible dissemination of tumor fragments. Moreover, morcellation into small fragments complicates the pathologist’s ability to give an accurate report. The use of open power morcellation also subjects the patient to a risk of damage to surrounding organs—usually due to the surgeon’s inexperience.

As I have said before, our challenge is to perform these surgeries using the safest techniques possible, given the current data and instrumentation.

OBG Management: Dr. Reich, you have a unique perspective on this issue, because you pioneered laparoscopic hysterectomy. How has uterine tissue extraction evolved since then? Do you think open power morcellation should remain an option?

Dr. Reich: Uterine tissue extraction has not evolved. The terms “laparoscopic hysterectomy” and “total laparoscopic hysterectomy” imply vaginal extraction using a scalpel, not abdominal extraction using a morcellator. Unfortunately there is no substitute for hard work using a #10 blade on a long handle and special vaginal retraction tools.

In 1983, I made a decision to stop performing laparotomy for all gynecologic procedures, including hysterectomy, myomectomy, urology, oncology, abscesses, extensive adhesions, and rectovaginal endometriosis. I was an accomplished vaginal surgeon at that time, as well as a one-handed laparoscopic surgeon, operating while looking through the scope with one eye.

Interest in a laparoscopic approach to hysterectomy began with my presentations about laparoscopic hysterectomy in January 1988. At that time I had over 10 years of experience doing what is now called laparoscopic-assisted vaginal hysterectomy.

I wrote extensively about specimen removal using a scalpel before electronic power morcellators were available. Since then, I have asked those using power morcellators to stop calling their operation a laparoscopic hysterectomy, as it has more in common with an abdominal-extraction hysterectomy.

I have never advocated removing the uterus using power morcellators, and I still believe that most specimens can be removed vaginally without the spray of pieces of the specimen around the peritoneal cavity that occurs with power morcellation. This goes for hysterectomy involving a large uterus, myomectomy through a culdotomy incision, and removal of the uterine fundus after supracervical hysterectomy. (It is irresponsible to use expensive power morcellation to remove small supracervical hysterectomy specimens.) It is time to get back to learning and teaching vaginal morcellation, although I readily admit it is time consuming.

Nevertheless, I believe power morcellation should remain an option. Recent laparoscopic fellowship trainees know only this technique, which is still better than a return to mutilation by laparotomy.

Gynecology is a frustrating profession—30 years of MIS as a sideshow. General surgery has rapidly adopted a laparoscopic approach to most operations, after gynecologists taught them. Today most ­gynecologists do not do advanced laparoscopic surgery and would love to get back to open incision laparotomy for their operations. We cannot go back.

OBG Management: Dr. Wertheim and Dr. Reich, do your personal views of the morcellation issue differ at all from the official views of professional societies?

Dr. Wertheim: Yes. However, before I share them, I’d like to emphasize that the views I’m about to express are mine and mine only, not those of the AAGL or its task force.

The issue of uterine extraction is a highly emotional and political issue, about which there are few good data.

Abundant Level 1 data strongly support a vaginal or laparoscopic approach for benign hysterectomy when possible. ACOG and AAGL have issued position papers supporting these approaches for benign hysterectomies. Gynecologic surgeons and other surgical specialists have embraced MIS because it is safer, offers faster recovery, produces less postoperative pain, and has fewer complications than open surgery. However, AAGL has maintained for several years that morcellation is contraindicated in cases where uterine malignancy is either known or suspected.

The dilemma with open power morcellation is that even with our best diagnostic tools, the rare uterine sarcoma cannot always be definitively ruled out preoperatively. Endometrial cancer usually can be diagnosed before surgery. However, rare subtypes such as sarcomas are more difficult to reliably diagnose preoperatively, and risk factors for uterine sarcomas are not nearly as well understood as those for endometrial cancer.

I do agree with the FDA’s cautionary statement on April 17, which pointedly prohibits power morcellation for women with suspected precancer or known cancer of the gynecologic organs.² However, the AAGL Task Force critically reviewed about 120 articles, including the studies assessed by the FDA. Concerns arose regarding the FDA’s interpretation of the data. Due to a number of deficiencies in these studies, some of the conclusions of the FDA may not be completely accurate. The studies analyzed by the FDA were not stratified by risk factors for sarcoma and were not necessarily performed in a setting of reproductive-aged women with presumed fibroids.

Dr. Reich: Here are my personal views about the sarcoma problem and I am sure they differ from the official views:

• Laparoscopic hysterectomy should always mean vaginal extraction unless a less disfiguring site can be discovered; power morcellation implies minilaparotomy and should be renamed to reflect that fact.
• Power morcellation must be differentiated from vaginal and minilaparotomy scalpel morcellation, especially in the media. Vaginal hysterectomy has entailed vaginal scalpel morcellation with successful outcomes for more than 100 years.
• Remember that most gynecologic cancers are approached using the laparoscope today. This certainly includes cervical and endometrial cancer and some ovarian cancers. (For example, one of my neighbors is a 25-year survivor of laparoscopically treated bilateral ovarian cancer who refused laparotomy!)
• I have removed sarcomas by vaginal morcellation during laparoscopic hysterectomy and laparoscopic myomectomy with no late sequelae. In fact, most cervical cancer surgery is done by laparoscopic surgery today. And even an open laparotomy hysterectomy can spread a sarcoma.
• The current morcellation debate arose when a single case of disseminated leiomyosarcoma became highly publicized. It involved a prominent physician whose leiomyosarcoma was unknown to her initial surgeon, and the malignancy was upstaged after the use of power morcellation during hysterectomy. After this case was covered in the media, other cases began to be reported in the lay press as well, some of which predated the publicized case. The truth is, regrettably, that sarcomas carry poor prognoses even when specimens are removed intact. And we don’t know much about the sarcoma that started this debate. Was it mild or aggressive? How many mitotic figures were there per high-powered field? And what was found macroscopicallyand microscopically at the subsequent laparotomy? We on the AAGL Task Force do not know the answers to these questions, although at least some of these variables are reported in other published cases. And because this case is likely to have a powerful effect on MIS in our country and the rest of the world, it is my opinion that we need to know these details.

What is your preferred surgical approach?
OBG Management: Do you perform open power morcellation in selected patients?

Dr. Wertheim: Even though I have performed morcellation with a scalpel transvaginally or through a mini-laparotomy incision for many years, I have never used open power morcellation because of the risk of leaving behind benign or malignant tissue fragments. Morcellation with a scalpel is easily learned and can be performed as quickly as power morcellation. Morcellation with a scalpel produces much larger pieces than with power morcellation. This probably markedly decreases the loss of fragments. I cannot make a definitive statement regarding cell loss, however. Until we have improved instrumentation and are better able to make a preoperative diagnosis of sarcoma, I’m going to rule out risk factors identified by the AAGL Task Force, do the appropriate work-up, and continue to morcellate with a scalpel, placing the specimen in a bag, if technically possible.

Dr. Reich: As I mentioned, I am a vaginal scalpel morcellator. I tried power morcellation when it first was developed but was never a fan. The same techniques used for vaginal extraction using a coring maneuver can be used abdominally through the umbilicus or a 1- or 2-cm trocar site.

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The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy has been in the limelight in 2014—particularly morcellation performed in an “open” fashion (without use of a protective bag). Concerns about the dispersion of tissue throughout the peritoneal cavity—including the risk of disseminating tissue from leiomyosarcoma, a rare but deadly cancer—have drawn statements from the American College of Obstetricians and Gynecologists (ACOG), the AAGL, the US Food and Drug Administration (FDA), and others, cautioning against the use of open power morcellation in women with a known or suspected malignancy.

In July 2014, the FDA convened a two-day hearing of the Obstetrics and Gynecology Devices Panel (one of the panels in its Medical Devices Advisory Committee) to consider whether power morcellation should remain an option and, if so, what restrictions or labeling might be recommended.

In advance of the FDA hearing, OBG Management invited two experts in women’s health to explore the options more deeply and address the future of minimally invasive surgery (MIS): Ray A. Wertheim, MD, Director of the AAGL Center of Excellence Minimally Invasive Gynecology Program at Inova Fair Oaks Hospital in Fairfax, Virginia, and Harry Reich, MD, widely known as the first surgeon to perform laparoscopic hysterectomy, among other achievements. Both Dr. Wertheim and Dr. Reich were members of the AAGL Tissue Extraction Task Force.

In this Q&A, Dr. Wertheim and Dr. Reich discuss:

• options for tissue extraction going forward
• the importance of continuing to offer minimally invasive surgical approaches
• the need to educate surgeons about the safest approaches to tissue extraction.

Both surgeons believe that power morcellation should remain an option for selected cases, although neither performs the technique himself. Both surgeons also believe that minimally invasive approaches to hysterectomy and myomectomy are here to stay and should continue to be used whenever possible.

AAGL convened an impartial expert panel
OBG Management: Dr. Wertheim, could you tell us a little about the AAGL position statement on the use of power morcellation for uterine tissue extraction at hysterectomy or myomectomy, since you were on the task force that researched and wrote it?¹

Dr. Wertheim: AAGL convened its task force to conduct a critical appraisal of the existing evidence related to the practice of uterine extraction in the setting of hysterectomy and myomectomy. Areas in need of further investigation also were identified.

The task force consisted of experts who had no conflicts, were not allowed to discuss or review findings with anyone, and were not reimbursed for their time. Our review is the most complete report to date, more comprehensive than the current reports from the FDA, ACOG, the Society of Gynecologic Oncology (SGO), and the American Urogynecologic Society (AUGS).

Interestingly, AAGL, ACOG, SGO, and AUGS all reached the same conclusion: All existing methods of tissue extraction have benefits and risks that must be balanced.

OBG Management: How did the AAGL Task Force assess the evidence?

Dr. Wertheim: The quality of evidence and strength of recommendations were assessed using US Preventive Services Task Force guidelines. There are very few good data on the issue of power morcellation for uterine tissue extraction, especially in regard to leiomyosarcoma. One needs to be careful making recommendations without good data.

Related article: First large study on risk of cancer spread using power morcellation. Janelle Yates (News for your Practice; August 2014)

At this time, we do not believe there is a single method of tissue extraction that can protect all patients. Therefore, all current methods should remain available. We believe that an understanding of the issues will allow surgeons, hospitals, and patients to make the appropriate informed choices regarding tissue extraction for individual patients undergoing uterine surgery.

How to manage tissue extraction going forward
OBG Management: Regardless of the FDA’s final decision, what should the gynecologic specialty be doing to avoid disseminating uterine tissue in the peritoneal cavity, particularly leiomyosarcoma?

Dr. Wertheim: MIS is a wonderful advancement in women’s health care. All surgical specialties are moving toward MIS. Our challenge is to perform it as safely as possible, given the data and instrumentation available.

In regard to leiomyosarcoma, because we lack the ability to accurately make the diagnosis preoperatively, we’ve identified risk factors that should be taken into consideration. They include advanced age, a history of radiation or tamoxifen use, black race, hereditary leiomyomatosis, renal cell carcinoma syndrome, and survival of childhood retinoblastoma.

At this time, we have specimen-retrieval bags that can be used with power morcellation. However, it takes skill to be able to place a large specimen inside a bag without injuring surrounding organs due to limited visibility.

Education, at the hospital and national level, is in the works
OBG Management: How should we go about educating surgeons about MIS alternatives to open power morcellation?

Dr. Wertheim: In my hospital, we are mentoring surgeons to help them gain the new skills needed. In addition, I plan to give a grand rounds presentation on tissue extraction for hospitals in northern Virginia and also would like to offer a course in the near future. I’m also hoping that we’ll be able to offer courses around the country before the annual AAGL meeting this November.

At the annual AAGL meeting, the subject will be discussed at length, with an emphasis on identifying risk factors and conducting appropriate preoperative testing, with workshops likely to teach the skills needed to perform these surgeries as safely as possible.

Why a return to reliance on laparotomy would be unwise
OBG Management: Given all the concerns expressed recently about open power morcellation, do you think some surgeons will revert to abdominal hysterectomy rather than rely on MIS? Would such a move be safer than power morcellation?

Dr. Wertheim: That would be a disaster for women. Very reliable data have shown that MIS is safer than open surgery, with much quicker recovery. Almost all of my patients are discharged within 3 hours after surgery, and most no longer require pain medications other than nonsteroidal anti-inflammatory drugs by postoperative day 2. They’re usually back to work within 2 weeks.

We have worked long and hard to develop skills and instrumentation required to perform MIS safely—but nothing replaces good judgment. In some cases, laparotomy or conversion to a laparotomy may be indicated.

New instrumentation is needed and is being developed. In the meantime, my personal bias is to rule out risk factors for malignancy and continue to morcellate with a scalpel, preferably inside a bag. After all, we know that with open power morcellation, fragments and cells are usually left behind regardless of inspection and irrigation. These fragments may cause leiomyomatosis, endometriosis, bowel obstruction, sepsis, and possible dissemination of tumor fragments. Moreover, morcellation into small fragments complicates the pathologist’s ability to give an accurate report. The use of open power morcellation also subjects the patient to a risk of damage to surrounding organs—usually due to the surgeon’s inexperience.

As I have said before, our challenge is to perform these surgeries using the safest techniques possible, given the current data and instrumentation.

OBG Management: Dr. Reich, you have a unique perspective on this issue, because you pioneered laparoscopic hysterectomy. How has uterine tissue extraction evolved since then? Do you think open power morcellation should remain an option?

Dr. Reich: Uterine tissue extraction has not evolved. The terms “laparoscopic hysterectomy” and “total laparoscopic hysterectomy” imply vaginal extraction using a scalpel, not abdominal extraction using a morcellator. Unfortunately there is no substitute for hard work using a #10 blade on a long handle and special vaginal retraction tools.

In 1983, I made a decision to stop performing laparotomy for all gynecologic procedures, including hysterectomy, myomectomy, urology, oncology, abscesses, extensive adhesions, and rectovaginal endometriosis. I was an accomplished vaginal surgeon at that time, as well as a one-handed laparoscopic surgeon, operating while looking through the scope with one eye.

Interest in a laparoscopic approach to hysterectomy began with my presentations about laparoscopic hysterectomy in January 1988. At that time I had over 10 years of experience doing what is now called laparoscopic-assisted vaginal hysterectomy.

I wrote extensively about specimen removal using a scalpel before electronic power morcellators were available. Since then, I have asked those using power morcellators to stop calling their operation a laparoscopic hysterectomy, as it has more in common with an abdominal-extraction hysterectomy.

I have never advocated removing the uterus using power morcellators, and I still believe that most specimens can be removed vaginally without the spray of pieces of the specimen around the peritoneal cavity that occurs with power morcellation. This goes for hysterectomy involving a large uterus, myomectomy through a culdotomy incision, and removal of the uterine fundus after supracervical hysterectomy. (It is irresponsible to use expensive power morcellation to remove small supracervical hysterectomy specimens.) It is time to get back to learning and teaching vaginal morcellation, although I readily admit it is time consuming.

Nevertheless, I believe power morcellation should remain an option. Recent laparoscopic fellowship trainees know only this technique, which is still better than a return to mutilation by laparotomy.

Gynecology is a frustrating profession—30 years of MIS as a sideshow. General surgery has rapidly adopted a laparoscopic approach to most operations, after gynecologists taught them. Today most ­gynecologists do not do advanced laparoscopic surgery and would love to get back to open incision laparotomy for their operations. We cannot go back.

OBG Management: Dr. Wertheim and Dr. Reich, do your personal views of the morcellation issue differ at all from the official views of professional societies?

Dr. Wertheim: Yes. However, before I share them, I’d like to emphasize that the views I’m about to express are mine and mine only, not those of the AAGL or its task force.

The issue of uterine extraction is a highly emotional and political issue, about which there are few good data.

Abundant Level 1 data strongly support a vaginal or laparoscopic approach for benign hysterectomy when possible. ACOG and AAGL have issued position papers supporting these approaches for benign hysterectomies. Gynecologic surgeons and other surgical specialists have embraced MIS because it is safer, offers faster recovery, produces less postoperative pain, and has fewer complications than open surgery. However, AAGL has maintained for several years that morcellation is contraindicated in cases where uterine malignancy is either known or suspected.

The dilemma with open power morcellation is that even with our best diagnostic tools, the rare uterine sarcoma cannot always be definitively ruled out preoperatively. Endometrial cancer usually can be diagnosed before surgery. However, rare subtypes such as sarcomas are more difficult to reliably diagnose preoperatively, and risk factors for uterine sarcomas are not nearly as well understood as those for endometrial cancer.

I do agree with the FDA’s cautionary statement on April 17, which pointedly prohibits power morcellation for women with suspected precancer or known cancer of the gynecologic organs.² However, the AAGL Task Force critically reviewed about 120 articles, including the studies assessed by the FDA. Concerns arose regarding the FDA’s interpretation of the data. Due to a number of deficiencies in these studies, some of the conclusions of the FDA may not be completely accurate. The studies analyzed by the FDA were not stratified by risk factors for sarcoma and were not necessarily performed in a setting of reproductive-aged women with presumed fibroids.

Dr. Reich: Here are my personal views about the sarcoma problem and I am sure they differ from the official views:

• Laparoscopic hysterectomy should always mean vaginal extraction unless a less disfiguring site can be discovered; power morcellation implies minilaparotomy and should be renamed to reflect that fact.
• Power morcellation must be differentiated from vaginal and minilaparotomy scalpel morcellation, especially in the media. Vaginal hysterectomy has entailed vaginal scalpel morcellation with successful outcomes for more than 100 years.
• Remember that most gynecologic cancers are approached using the laparoscope today. This certainly includes cervical and endometrial cancer and some ovarian cancers. (For example, one of my neighbors is a 25-year survivor of laparoscopically treated bilateral ovarian cancer who refused laparotomy!)
• I have removed sarcomas by vaginal morcellation during laparoscopic hysterectomy and laparoscopic myomectomy with no late sequelae. In fact, most cervical cancer surgery is done by laparoscopic surgery today. And even an open laparotomy hysterectomy can spread a sarcoma.
• The current morcellation debate arose when a single case of disseminated leiomyosarcoma became highly publicized. It involved a prominent physician whose leiomyosarcoma was unknown to her initial surgeon, and the malignancy was upstaged after the use of power morcellation during hysterectomy. After this case was covered in the media, other cases began to be reported in the lay press as well, some of which predated the publicized case. The truth is, regrettably, that sarcomas carry poor prognoses even when specimens are removed intact. And we don’t know much about the sarcoma that started this debate. Was it mild or aggressive? How many mitotic figures were there per high-powered field? And what was found macroscopicallyand microscopically at the subsequent laparotomy? We on the AAGL Task Force do not know the answers to these questions, although at least some of these variables are reported in other published cases. And because this case is likely to have a powerful effect on MIS in our country and the rest of the world, it is my opinion that we need to know these details.

What is your preferred surgical approach?
OBG Management: Do you perform open power morcellation in selected patients?

Dr. Wertheim: Even though I have performed morcellation with a scalpel transvaginally or through a mini-laparotomy incision for many years, I have never used open power morcellation because of the risk of leaving behind benign or malignant tissue fragments. Morcellation with a scalpel is easily learned and can be performed as quickly as power morcellation. Morcellation with a scalpel produces much larger pieces than with power morcellation. This probably markedly decreases the loss of fragments. I cannot make a definitive statement regarding cell loss, however. Until we have improved instrumentation and are better able to make a preoperative diagnosis of sarcoma, I’m going to rule out risk factors identified by the AAGL Task Force, do the appropriate work-up, and continue to morcellate with a scalpel, placing the specimen in a bag, if technically possible.

Dr. Reich: As I mentioned, I am a vaginal scalpel morcellator. I tried power morcellation when it first was developed but was never a fan. The same techniques used for vaginal extraction using a coring maneuver can be used abdominally through the umbilicus or a 1- or 2-cm trocar site.

WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: [email protected] 

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy has been in the limelight in 2014—particularly morcellation performed in an “open” fashion (without use of a protective bag). Concerns about the dispersion of tissue throughout the peritoneal cavity—including the risk of disseminating tissue from leiomyosarcoma, a rare but deadly cancer—have drawn statements from the American College of Obstetricians and Gynecologists (ACOG), the AAGL, the US Food and Drug Administration (FDA), and others, cautioning against the use of open power morcellation in women with a known or suspected malignancy.

In July 2014, the FDA convened a two-day hearing of the Obstetrics and Gynecology Devices Panel (one of the panels in its Medical Devices Advisory Committee) to consider whether power morcellation should remain an option and, if so, what restrictions or labeling might be recommended.

In advance of the FDA hearing, OBG Management invited two experts in women’s health to explore the options more deeply and address the future of minimally invasive surgery (MIS): Ray A. Wertheim, MD, Director of the AAGL Center of Excellence Minimally Invasive Gynecology Program at Inova Fair Oaks Hospital in Fairfax, Virginia, and Harry Reich, MD, widely known as the first surgeon to perform laparoscopic hysterectomy, among other achievements. Both Dr. Wertheim and Dr. Reich were members of the AAGL Tissue Extraction Task Force.

In this Q&A, Dr. Wertheim and Dr. Reich discuss:

• options for tissue extraction going forward
• the importance of continuing to offer minimally invasive surgical approaches
• the need to educate surgeons about the safest approaches to tissue extraction.

Both surgeons believe that power morcellation should remain an option for selected cases, although neither performs the technique himself. Both surgeons also believe that minimally invasive approaches to hysterectomy and myomectomy are here to stay and should continue to be used whenever possible.

AAGL convened an impartial expert panel
OBG Management: Dr. Wertheim, could you tell us a little about the AAGL position statement on the use of power morcellation for uterine tissue extraction at hysterectomy or myomectomy, since you were on the task force that researched and wrote it?¹

Dr. Wertheim: AAGL convened its task force to conduct a critical appraisal of the existing evidence related to the practice of uterine extraction in the setting of hysterectomy and myomectomy. Areas in need of further investigation also were identified.

The task force consisted of experts who had no conflicts, were not allowed to discuss or review findings with anyone, and were not reimbursed for their time. Our review is the most complete report to date, more comprehensive than the current reports from the FDA, ACOG, the Society of Gynecologic Oncology (SGO), and the American Urogynecologic Society (AUGS).

Interestingly, AAGL, ACOG, SGO, and AUGS all reached the same conclusion: All existing methods of tissue extraction have benefits and risks that must be balanced.

OBG Management: How did the AAGL Task Force assess the evidence?

Dr. Wertheim: The quality of evidence and strength of recommendations were assessed using US Preventive Services Task Force guidelines. There are very few good data on the issue of power morcellation for uterine tissue extraction, especially in regard to leiomyosarcoma. One needs to be careful making recommendations without good data.

Related article: First large study on risk of cancer spread using power morcellation. Janelle Yates (News for your Practice; August 2014)

At this time, we do not believe there is a single method of tissue extraction that can protect all patients. Therefore, all current methods should remain available. We believe that an understanding of the issues will allow surgeons, hospitals, and patients to make the appropriate informed choices regarding tissue extraction for individual patients undergoing uterine surgery.

How to manage tissue extraction going forward
OBG Management: Regardless of the FDA’s final decision, what should the gynecologic specialty be doing to avoid disseminating uterine tissue in the peritoneal cavity, particularly leiomyosarcoma?

Dr. Wertheim: MIS is a wonderful advancement in women’s health care. All surgical specialties are moving toward MIS. Our challenge is to perform it as safely as possible, given the data and instrumentation available.

In regard to leiomyosarcoma, because we lack the ability to accurately make the diagnosis preoperatively, we’ve identified risk factors that should be taken into consideration. They include advanced age, a history of radiation or tamoxifen use, black race, hereditary leiomyomatosis, renal cell carcinoma syndrome, and survival of childhood retinoblastoma.

At this time, we have specimen-retrieval bags that can be used with power morcellation. However, it takes skill to be able to place a large specimen inside a bag without injuring surrounding organs due to limited visibility.

Education, at the hospital and national level, is in the works
OBG Management: How should we go about educating surgeons about MIS alternatives to open power morcellation?

Dr. Wertheim: In my hospital, we are mentoring surgeons to help them gain the new skills needed. In addition, I plan to give a grand rounds presentation on tissue extraction for hospitals in northern Virginia and also would like to offer a course in the near future. I’m also hoping that we’ll be able to offer courses around the country before the annual AAGL meeting this November.

At the annual AAGL meeting, the subject will be discussed at length, with an emphasis on identifying risk factors and conducting appropriate preoperative testing, with workshops likely to teach the skills needed to perform these surgeries as safely as possible.

Why a return to reliance on laparotomy would be unwise
OBG Management: Given all the concerns expressed recently about open power morcellation, do you think some surgeons will revert to abdominal hysterectomy rather than rely on MIS? Would such a move be safer than power morcellation?

Dr. Wertheim: That would be a disaster for women. Very reliable data have shown that MIS is safer than open surgery, with much quicker recovery. Almost all of my patients are discharged within 3 hours after surgery, and most no longer require pain medications other than nonsteroidal anti-inflammatory drugs by postoperative day 2. They’re usually back to work within 2 weeks.

We have worked long and hard to develop skills and instrumentation required to perform MIS safely—but nothing replaces good judgment. In some cases, laparotomy or conversion to a laparotomy may be indicated.

New instrumentation is needed and is being developed. In the meantime, my personal bias is to rule out risk factors for malignancy and continue to morcellate with a scalpel, preferably inside a bag. After all, we know that with open power morcellation, fragments and cells are usually left behind regardless of inspection and irrigation. These fragments may cause leiomyomatosis, endometriosis, bowel obstruction, sepsis, and possible dissemination of tumor fragments. Moreover, morcellation into small fragments complicates the pathologist’s ability to give an accurate report. The use of open power morcellation also subjects the patient to a risk of damage to surrounding organs—usually due to the surgeon’s inexperience.

As I have said before, our challenge is to perform these surgeries using the safest techniques possible, given the current data and instrumentation.

OBG Management: Dr. Reich, you have a unique perspective on this issue, because you pioneered laparoscopic hysterectomy. How has uterine tissue extraction evolved since then? Do you think open power morcellation should remain an option?

Dr. Reich: Uterine tissue extraction has not evolved. The terms “laparoscopic hysterectomy” and “total laparoscopic hysterectomy” imply vaginal extraction using a scalpel, not abdominal extraction using a morcellator. Unfortunately there is no substitute for hard work using a #10 blade on a long handle and special vaginal retraction tools.

In 1983, I made a decision to stop performing laparotomy for all gynecologic procedures, including hysterectomy, myomectomy, urology, oncology, abscesses, extensive adhesions, and rectovaginal endometriosis. I was an accomplished vaginal surgeon at that time, as well as a one-handed laparoscopic surgeon, operating while looking through the scope with one eye.

Interest in a laparoscopic approach to hysterectomy began with my presentations about laparoscopic hysterectomy in January 1988. At that time I had over 10 years of experience doing what is now called laparoscopic-assisted vaginal hysterectomy.

I wrote extensively about specimen removal using a scalpel before electronic power morcellators were available. Since then, I have asked those using power morcellators to stop calling their operation a laparoscopic hysterectomy, as it has more in common with an abdominal-extraction hysterectomy.

I have never advocated removing the uterus using power morcellators, and I still believe that most specimens can be removed vaginally without the spray of pieces of the specimen around the peritoneal cavity that occurs with power morcellation. This goes for hysterectomy involving a large uterus, myomectomy through a culdotomy incision, and removal of the uterine fundus after supracervical hysterectomy. (It is irresponsible to use expensive power morcellation to remove small supracervical hysterectomy specimens.) It is time to get back to learning and teaching vaginal morcellation, although I readily admit it is time consuming.

Nevertheless, I believe power morcellation should remain an option. Recent laparoscopic fellowship trainees know only this technique, which is still better than a return to mutilation by laparotomy.

Gynecology is a frustrating profession—30 years of MIS as a sideshow. General surgery has rapidly adopted a laparoscopic approach to most operations, after gynecologists taught them. Today most ­gynecologists do not do advanced laparoscopic surgery and would love to get back to open incision laparotomy for their operations. We cannot go back.

OBG Management: Dr. Wertheim and Dr. Reich, do your personal views of the morcellation issue differ at all from the official views of professional societies?

Dr. Wertheim: Yes. However, before I share them, I’d like to emphasize that the views I’m about to express are mine and mine only, not those of the AAGL or its task force.

The issue of uterine extraction is a highly emotional and political issue, about which there are few good data.

Abundant Level 1 data strongly support a vaginal or laparoscopic approach for benign hysterectomy when possible. ACOG and AAGL have issued position papers supporting these approaches for benign hysterectomies. Gynecologic surgeons and other surgical specialists have embraced MIS because it is safer, offers faster recovery, produces less postoperative pain, and has fewer complications than open surgery. However, AAGL has maintained for several years that morcellation is contraindicated in cases where uterine malignancy is either known or suspected.

The dilemma with open power morcellation is that even with our best diagnostic tools, the rare uterine sarcoma cannot always be definitively ruled out preoperatively. Endometrial cancer usually can be diagnosed before surgery. However, rare subtypes such as sarcomas are more difficult to reliably diagnose preoperatively, and risk factors for uterine sarcomas are not nearly as well understood as those for endometrial cancer.

I do agree with the FDA’s cautionary statement on April 17, which pointedly prohibits power morcellation for women with suspected precancer or known cancer of the gynecologic organs.² However, the AAGL Task Force critically reviewed about 120 articles, including the studies assessed by the FDA. Concerns arose regarding the FDA’s interpretation of the data. Due to a number of deficiencies in these studies, some of the conclusions of the FDA may not be completely accurate. The studies analyzed by the FDA were not stratified by risk factors for sarcoma and were not necessarily performed in a setting of reproductive-aged women with presumed fibroids.

Dr. Reich: Here are my personal views about the sarcoma problem and I am sure they differ from the official views:

• Laparoscopic hysterectomy should always mean vaginal extraction unless a less disfiguring site can be discovered; power morcellation implies minilaparotomy and should be renamed to reflect that fact.
• Power morcellation must be differentiated from vaginal and minilaparotomy scalpel morcellation, especially in the media. Vaginal hysterectomy has entailed vaginal scalpel morcellation with successful outcomes for more than 100 years.
• Remember that most gynecologic cancers are approached using the laparoscope today. This certainly includes cervical and endometrial cancer and some ovarian cancers. (For example, one of my neighbors is a 25-year survivor of laparoscopically treated bilateral ovarian cancer who refused laparotomy!)
• I have removed sarcomas by vaginal morcellation during laparoscopic hysterectomy and laparoscopic myomectomy with no late sequelae. In fact, most cervical cancer surgery is done by laparoscopic surgery today. And even an open laparotomy hysterectomy can spread a sarcoma.
• The current morcellation debate arose when a single case of disseminated leiomyosarcoma became highly publicized. It involved a prominent physician whose leiomyosarcoma was unknown to her initial surgeon, and the malignancy was upstaged after the use of power morcellation during hysterectomy. After this case was covered in the media, other cases began to be reported in the lay press as well, some of which predated the publicized case. The truth is, regrettably, that sarcomas carry poor prognoses even when specimens are removed intact. And we don’t know much about the sarcoma that started this debate. Was it mild or aggressive? How many mitotic figures were there per high-powered field? And what was found macroscopicallyand microscopically at the subsequent laparotomy? We on the AAGL Task Force do not know the answers to these questions, although at least some of these variables are reported in other published cases. And because this case is likely to have a powerful effect on MIS in our country and the rest of the world, it is my opinion that we need to know these details.

What is your preferred surgical approach?
OBG Management: Do you perform open power morcellation in selected patients?

Dr. Wertheim: Even though I have performed morcellation with a scalpel transvaginally or through a mini-laparotomy incision for many years, I have never used open power morcellation because of the risk of leaving behind benign or malignant tissue fragments. Morcellation with a scalpel is easily learned and can be performed as quickly as power morcellation. Morcellation with a scalpel produces much larger pieces than with power morcellation. This probably markedly decreases the loss of fragments. I cannot make a definitive statement regarding cell loss, however. Until we have improved instrumentation and are better able to make a preoperative diagnosis of sarcoma, I’m going to rule out risk factors identified by the AAGL Task Force, do the appropriate work-up, and continue to morcellate with a scalpel, placing the specimen in a bag, if technically possible.

Dr. Reich: As I mentioned, I am a vaginal scalpel morcellator. I tried power morcellation when it first was developed but was never a fan. The same techniques used for vaginal extraction using a coring maneuver can be used abdominally through the umbilicus or a 1- or 2-cm trocar site.

WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: [email protected] 

Twenty years ago Dr. Joseph Alpert and I published an editorial suggesting that we were training too many cardiologists and that we should begin to decrease the existing training programs. It was written in anticipation of the expansion of health maintenance organizations and the Clinton health care initiatives, neither of which occurred (Am. J. Cardiol. 1994;74:394-5). Our opinions were met with universal disdain among our cardiology colleagues.

However, what did take place over the next 15 years was the creation of a cardiology "boom," inflated by an expansion of cardiology services with coronary stents and multiple imaging techniques, which succeeded in making work for newly trained cardiologists. Most of these procedures, with few exceptions, had little or no impact on the quality of care but did generate a significant increase in cost. From 1995 to 2012, an additional 7,000 cardiologists became members of the American College of Cardiology, swelling its ranks from 21,000 to 28,000 members. Workforce projection in the early 21st century suggested that there would be a continuing need for cardiology specialists well into 2025. These projections were based on the aging of the population and gave little attention to the potential future change in health care financing.

But in fact, changes did occur, and the cardiology boom has been deflated, not like the 2008 deflation of the housing boom, but it is clear that some of the gas has been let out, and the boom will continue to deflate in the future. A recent editorial (J. Am. Coll. Cardiol. 2014,63;1927-8) authored by the ACC leaders suggests that major adjustments in career goals of graduating trainees will have to be made in order to deal with the change in the marketplace. The major change in the reimbursement for outpatient procedures that favored hospital services created a flight of practicing physicians from private to hospital-based practice. The federal government and private insurers can now monitor practice patterns and the utilizations of services more closely, and this has led to a significant decrease in these procedures. At the same time, the conversion of your friendly local hospital to a corporate conglomerate has opened the door for hospital administrators to squeeze cost centers like cardiology in order to improve the bottom line.

The new emphasis on physician participation in cost control, as manifested by the move to medical homes and accountable care organizations, emphasizes quality improvement over quantity billing, where doctors can benefit financially from cost savings. Patients are also becoming more concerned about their own role in medical costs as they begin to face increases in deductible costs. The age of fee-for-service payment is fast coming to an end. We are moving away from high-cost care that led to the boom to efficient care based on value payment models.

As medicine, and particularly cardiology, moves further into the 21st century it is clear that we are victims of our own technology. It is difficult to predict the future when so many countercurrents are in effect in our profession. Joe Alpert and I missed the target by about 20 years, but we could never have anticipated the magnitude of ebb and flow of workforce tides. Many of us presumed that the medical profession would be free of the changes in economy and technology. We are learning now that we are not immune to those changes.

To my readers: After writing this column for almost 18 years, I have decided to take a long summer vacation. I plan to be back in the fall but writing less frequently and sharing this wonderful platform with others. I thank you all for the many comments that I have received through the years, both positive and negative. I also want to thank my editor, Catherine Hackett, who has always encouraged me to speak out without any constraint.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Twenty years ago Dr. Joseph Alpert and I published an editorial suggesting that we were training too many cardiologists and that we should begin to decrease the existing training programs. It was written in anticipation of the expansion of health maintenance organizations and the Clinton health care initiatives, neither of which occurred (Am. J. Cardiol. 1994;74:394-5). Our opinions were met with universal disdain among our cardiology colleagues.

However, what did take place over the next 15 years was the creation of a cardiology "boom," inflated by an expansion of cardiology services with coronary stents and multiple imaging techniques, which succeeded in making work for newly trained cardiologists. Most of these procedures, with few exceptions, had little or no impact on the quality of care but did generate a significant increase in cost. From 1995 to 2012, an additional 7,000 cardiologists became members of the American College of Cardiology, swelling its ranks from 21,000 to 28,000 members. Workforce projection in the early 21st century suggested that there would be a continuing need for cardiology specialists well into 2025. These projections were based on the aging of the population and gave little attention to the potential future change in health care financing.

But in fact, changes did occur, and the cardiology boom has been deflated, not like the 2008 deflation of the housing boom, but it is clear that some of the gas has been let out, and the boom will continue to deflate in the future. A recent editorial (J. Am. Coll. Cardiol. 2014,63;1927-8) authored by the ACC leaders suggests that major adjustments in career goals of graduating trainees will have to be made in order to deal with the change in the marketplace. The major change in the reimbursement for outpatient procedures that favored hospital services created a flight of practicing physicians from private to hospital-based practice. The federal government and private insurers can now monitor practice patterns and the utilizations of services more closely, and this has led to a significant decrease in these procedures. At the same time, the conversion of your friendly local hospital to a corporate conglomerate has opened the door for hospital administrators to squeeze cost centers like cardiology in order to improve the bottom line.

The new emphasis on physician participation in cost control, as manifested by the move to medical homes and accountable care organizations, emphasizes quality improvement over quantity billing, where doctors can benefit financially from cost savings. Patients are also becoming more concerned about their own role in medical costs as they begin to face increases in deductible costs. The age of fee-for-service payment is fast coming to an end. We are moving away from high-cost care that led to the boom to efficient care based on value payment models.

As medicine, and particularly cardiology, moves further into the 21st century it is clear that we are victims of our own technology. It is difficult to predict the future when so many countercurrents are in effect in our profession. Joe Alpert and I missed the target by about 20 years, but we could never have anticipated the magnitude of ebb and flow of workforce tides. Many of us presumed that the medical profession would be free of the changes in economy and technology. We are learning now that we are not immune to those changes.

To my readers: After writing this column for almost 18 years, I have decided to take a long summer vacation. I plan to be back in the fall but writing less frequently and sharing this wonderful platform with others. I thank you all for the many comments that I have received through the years, both positive and negative. I also want to thank my editor, Catherine Hackett, who has always encouraged me to speak out without any constraint.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Twenty years ago Dr. Joseph Alpert and I published an editorial suggesting that we were training too many cardiologists and that we should begin to decrease the existing training programs. It was written in anticipation of the expansion of health maintenance organizations and the Clinton health care initiatives, neither of which occurred (Am. J. Cardiol. 1994;74:394-5). Our opinions were met with universal disdain among our cardiology colleagues.

However, what did take place over the next 15 years was the creation of a cardiology "boom," inflated by an expansion of cardiology services with coronary stents and multiple imaging techniques, which succeeded in making work for newly trained cardiologists. Most of these procedures, with few exceptions, had little or no impact on the quality of care but did generate a significant increase in cost. From 1995 to 2012, an additional 7,000 cardiologists became members of the American College of Cardiology, swelling its ranks from 21,000 to 28,000 members. Workforce projection in the early 21st century suggested that there would be a continuing need for cardiology specialists well into 2025. These projections were based on the aging of the population and gave little attention to the potential future change in health care financing.

But in fact, changes did occur, and the cardiology boom has been deflated, not like the 2008 deflation of the housing boom, but it is clear that some of the gas has been let out, and the boom will continue to deflate in the future. A recent editorial (J. Am. Coll. Cardiol. 2014,63;1927-8) authored by the ACC leaders suggests that major adjustments in career goals of graduating trainees will have to be made in order to deal with the change in the marketplace. The major change in the reimbursement for outpatient procedures that favored hospital services created a flight of practicing physicians from private to hospital-based practice. The federal government and private insurers can now monitor practice patterns and the utilizations of services more closely, and this has led to a significant decrease in these procedures. At the same time, the conversion of your friendly local hospital to a corporate conglomerate has opened the door for hospital administrators to squeeze cost centers like cardiology in order to improve the bottom line.

The new emphasis on physician participation in cost control, as manifested by the move to medical homes and accountable care organizations, emphasizes quality improvement over quantity billing, where doctors can benefit financially from cost savings. Patients are also becoming more concerned about their own role in medical costs as they begin to face increases in deductible costs. The age of fee-for-service payment is fast coming to an end. We are moving away from high-cost care that led to the boom to efficient care based on value payment models.

As medicine, and particularly cardiology, moves further into the 21st century it is clear that we are victims of our own technology. It is difficult to predict the future when so many countercurrents are in effect in our profession. Joe Alpert and I missed the target by about 20 years, but we could never have anticipated the magnitude of ebb and flow of workforce tides. Many of us presumed that the medical profession would be free of the changes in economy and technology. We are learning now that we are not immune to those changes.

To my readers: After writing this column for almost 18 years, I have decided to take a long summer vacation. I plan to be back in the fall but writing less frequently and sharing this wonderful platform with others. I thank you all for the many comments that I have received through the years, both positive and negative. I also want to thank my editor, Catherine Hackett, who has always encouraged me to speak out without any constraint.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Blood in bags and vials

Credit: Daniel Gay

Roughly 1 in 3000 English blood donors have hepatitis E virus (HEV) in their plasma, according to research published in The Lancet.

This suggests that about 1200 HEV-containing blood components may be transfused in England every year.

“HEV genotype 3 infections are widespread in the English population, including blood donors,” said study author Richard Tedder, MB ChB, of National Health Service Blood and Transplant in London.

“We estimate that between 80,000 and 100,000 human HEV infections are likely to have occurred in England during the year of our study.”

These figures seem to indicate a need for screening blood donations. But Dr Tedder and his colleagues found evidence suggesting a low overall burden of harm from transfusion-transmitted HEV.

The researchers retrospectively screened 225,000 individual blood donations collected in south east England between October 2012 and September 2013 for HEV RNA.

Seventy-nine donors—about 1 in 2848—were infected with genotype 3 HEV, which can spread directly from animals to humans. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused.

Follow-up of 43 exposed recipients showed that transmission had occurred in 18 (42%) patients.

Immunosuppression extended the duration of viremia in these patients, but 3 cleared their infection following a change in immunosuppressive therapy or after receiving ribavirin.

Ten of the patients developed prolonged or persistent infection. Transaminitis was common, and 1 patient developed hepatitis.

“Although rarely causing any acute illness, hepatitis E infections may become persistent in immunosuppressed patients, putting them at risk of future chronic liver disease, and a policy is needed to identify these persistently infected patients and provide them with appropriate antiviral treatment,” Dr Tedder said.

“However, our study indicates that the overall burden of harm resulting from transfusion-transmitted HEV is slight. Although, on a clinical basis alone, there appears no pressing need at this time for blood donations to be screened, a broader discussion over harm mitigation is now required.”

A related comment article in The Lancet suggested there is, in fact, a need for the systematic screening of blood components.

“The potential clinical results of blood-borne HEV infection should not be downplayed; in particular, the risk of serious complications and death exists,” wrote Jean-Michel Pawlotsky, MD, PhD, of Hôpital Henri Mondor in Créteil, France.

“Thus, on the basis of [the current] and other studies, I believe that systematic screening of blood components for markers of hepatitis E infection should be implemented in areas where HEV is endemic (eg, the European Union), based on HEV RNA detection.”

Blood in bags and vials

Credit: Daniel Gay

Roughly 1 in 3000 English blood donors have hepatitis E virus (HEV) in their plasma, according to research published in The Lancet.

This suggests that about 1200 HEV-containing blood components may be transfused in England every year.

“HEV genotype 3 infections are widespread in the English population, including blood donors,” said study author Richard Tedder, MB ChB, of National Health Service Blood and Transplant in London.

“We estimate that between 80,000 and 100,000 human HEV infections are likely to have occurred in England during the year of our study.”

These figures seem to indicate a need for screening blood donations. But Dr Tedder and his colleagues found evidence suggesting a low overall burden of harm from transfusion-transmitted HEV.

The researchers retrospectively screened 225,000 individual blood donations collected in south east England between October 2012 and September 2013 for HEV RNA.

Seventy-nine donors—about 1 in 2848—were infected with genotype 3 HEV, which can spread directly from animals to humans. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused.

Follow-up of 43 exposed recipients showed that transmission had occurred in 18 (42%) patients.

Immunosuppression extended the duration of viremia in these patients, but 3 cleared their infection following a change in immunosuppressive therapy or after receiving ribavirin.

Ten of the patients developed prolonged or persistent infection. Transaminitis was common, and 1 patient developed hepatitis.

“Although rarely causing any acute illness, hepatitis E infections may become persistent in immunosuppressed patients, putting them at risk of future chronic liver disease, and a policy is needed to identify these persistently infected patients and provide them with appropriate antiviral treatment,” Dr Tedder said.

“However, our study indicates that the overall burden of harm resulting from transfusion-transmitted HEV is slight. Although, on a clinical basis alone, there appears no pressing need at this time for blood donations to be screened, a broader discussion over harm mitigation is now required.”

A related comment article in The Lancet suggested there is, in fact, a need for the systematic screening of blood components.

“The potential clinical results of blood-borne HEV infection should not be downplayed; in particular, the risk of serious complications and death exists,” wrote Jean-Michel Pawlotsky, MD, PhD, of Hôpital Henri Mondor in Créteil, France.

“Thus, on the basis of [the current] and other studies, I believe that systematic screening of blood components for markers of hepatitis E infection should be implemented in areas where HEV is endemic (eg, the European Union), based on HEV RNA detection.”

Blood in bags and vials

Credit: Daniel Gay

Roughly 1 in 3000 English blood donors have hepatitis E virus (HEV) in their plasma, according to research published in The Lancet.

This suggests that about 1200 HEV-containing blood components may be transfused in England every year.

“HEV genotype 3 infections are widespread in the English population, including blood donors,” said study author Richard Tedder, MB ChB, of National Health Service Blood and Transplant in London.

“We estimate that between 80,000 and 100,000 human HEV infections are likely to have occurred in England during the year of our study.”

These figures seem to indicate a need for screening blood donations. But Dr Tedder and his colleagues found evidence suggesting a low overall burden of harm from transfusion-transmitted HEV.

The researchers retrospectively screened 225,000 individual blood donations collected in south east England between October 2012 and September 2013 for HEV RNA.

Seventy-nine donors—about 1 in 2848—were infected with genotype 3 HEV, which can spread directly from animals to humans. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused.

Follow-up of 43 exposed recipients showed that transmission had occurred in 18 (42%) patients.

Immunosuppression extended the duration of viremia in these patients, but 3 cleared their infection following a change in immunosuppressive therapy or after receiving ribavirin.

Ten of the patients developed prolonged or persistent infection. Transaminitis was common, and 1 patient developed hepatitis.

“Although rarely causing any acute illness, hepatitis E infections may become persistent in immunosuppressed patients, putting them at risk of future chronic liver disease, and a policy is needed to identify these persistently infected patients and provide them with appropriate antiviral treatment,” Dr Tedder said.

“However, our study indicates that the overall burden of harm resulting from transfusion-transmitted HEV is slight. Although, on a clinical basis alone, there appears no pressing need at this time for blood donations to be screened, a broader discussion over harm mitigation is now required.”

A related comment article in The Lancet suggested there is, in fact, a need for the systematic screening of blood components.

“The potential clinical results of blood-borne HEV infection should not be downplayed; in particular, the risk of serious complications and death exists,” wrote Jean-Michel Pawlotsky, MD, PhD, of Hôpital Henri Mondor in Créteil, France.

“Thus, on the basis of [the current] and other studies, I believe that systematic screening of blood components for markers of hepatitis E infection should be implemented in areas where HEV is endemic (eg, the European Union), based on HEV RNA detection.”

Lab mice

Credit: Aaron Logan

Researchers say they’ve created a mouse model that provides the first in vivo evidence that epigenetic alterations alone can cause cancer.

They described the work in The Journal of Clinical Investigation.

“We knew that epigenetic changes are associated with cancer but didn’t know whether these were a cause or consequence of cancer,” said study author Lanlan Shen, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“Developing this new approach for ‘epigenetic engineering’ allowed us to test whether DNA methylation changes alone can drive cancer.”

Dr Shen and her colleagues focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a range of cancers. They devised an approach to engineer DNA methylation specifically to the mouse p16 promoter.

As intended, the engineered p16 promoter acted as a “methylation magnet.” As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers and reduced survival.

“This is not only the first in vivo evidence that epigenetic alteration alone can cause cancer,” Dr Shen said.

“This also has profound implications for future studies because epigenetic changes are potentially reversible. Our findings therefore both provide hope for new epigenetic therapies and validate a novel approach for testing them.”

Dr Shen also noted that this new approach could be widely useful because there are many other genes and diseases connected to epigenetics.

Just as genetic engineering has become a standard approach for studying how genetic mutations cause disease, epigenetic engineering will enable functional studies of epigenetics.

Lab mice

Credit: Aaron Logan

Researchers say they’ve created a mouse model that provides the first in vivo evidence that epigenetic alterations alone can cause cancer.

They described the work in The Journal of Clinical Investigation.

“We knew that epigenetic changes are associated with cancer but didn’t know whether these were a cause or consequence of cancer,” said study author Lanlan Shen, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“Developing this new approach for ‘epigenetic engineering’ allowed us to test whether DNA methylation changes alone can drive cancer.”

Dr Shen and her colleagues focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a range of cancers. They devised an approach to engineer DNA methylation specifically to the mouse p16 promoter.

As intended, the engineered p16 promoter acted as a “methylation magnet.” As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers and reduced survival.

“This is not only the first in vivo evidence that epigenetic alteration alone can cause cancer,” Dr Shen said.

“This also has profound implications for future studies because epigenetic changes are potentially reversible. Our findings therefore both provide hope for new epigenetic therapies and validate a novel approach for testing them.”

Dr Shen also noted that this new approach could be widely useful because there are many other genes and diseases connected to epigenetics.

Just as genetic engineering has become a standard approach for studying how genetic mutations cause disease, epigenetic engineering will enable functional studies of epigenetics.

Lab mice

Credit: Aaron Logan

Researchers say they’ve created a mouse model that provides the first in vivo evidence that epigenetic alterations alone can cause cancer.

They described the work in The Journal of Clinical Investigation.

“We knew that epigenetic changes are associated with cancer but didn’t know whether these were a cause or consequence of cancer,” said study author Lanlan Shen, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“Developing this new approach for ‘epigenetic engineering’ allowed us to test whether DNA methylation changes alone can drive cancer.”

Dr Shen and her colleagues focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a range of cancers. They devised an approach to engineer DNA methylation specifically to the mouse p16 promoter.

As intended, the engineered p16 promoter acted as a “methylation magnet.” As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers and reduced survival.

“This is not only the first in vivo evidence that epigenetic alteration alone can cause cancer,” Dr Shen said.

“This also has profound implications for future studies because epigenetic changes are potentially reversible. Our findings therefore both provide hope for new epigenetic therapies and validate a novel approach for testing them.”

Dr Shen also noted that this new approach could be widely useful because there are many other genes and diseases connected to epigenetics.

Just as genetic engineering has become a standard approach for studying how genetic mutations cause disease, epigenetic engineering will enable functional studies of epigenetics.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the National Initiative for Children’s Healthcare Quality, Boston, MA.

This month JCOM launches a series calling attention to 5 teams working to improve care for individuals with sickle cell disease and sickle cell trait in the Hemoglobinopathy Learning Collaborative (—Ed.)

Sickle cell disease affects close to 100,000 people in United States [1]. This condition is characterized by chronic anemia and unpredictable pain episodes beginning in early childhood and leading to changes in functioning, diminished health-related quality of life, end-organ damage, increased health care use, and in some cases early mortality [2–5]. Sickle cell disease is identified through universal newborn screening [6] and is found in one in 2474 newborn Americans [7], with Americans of African ancestry most frequently affected. It is estimated that over 2 million Americans are genetic carriers of the sickle cell gene.

Although there have been major advancements in sickle cell care within the past several decades, there still exist significant variations in care and mortality [8–14]. Ongoing strategies to improve patient access to efficacious treatments are essential to improve outcomes for individuals with sickle cell disease.

Recognizing the compelling need for a focused national effort to improve care for this population and the relative lack of private resources committed to it [15], Congress established 2 federal programs to enhance newborn screening and improve follow-up and care and outcomes for this population: the Sickle Cell Disease Newborn Screening Program in 2002 [16] and the Sickle Cell Disease Treatment Demonstration Program in 2004 [17]. The programs are funded by the Health Resources and Services Administration and administered by the National Initiative for Children’s Healthcare Quality (NICHQ)’s Working to Improve Sickle Cell Healthcare (WISCH) program [2]. NICHQ became the coordinating center for the programs in 2011 and 2010, respectively. Diverse grantees are now working together in a Hemoglobinopathy Learning Collaborative, coordinated and facilitated by NICHQ and its partners Boston Medical Center and the Sickle Cell Disease Association of America. The current rounds of funding continue through 2014 for the Sickle Cell Disease Treatment Demonstration Program and 2015 for the Sickle Cell Disease Newborn Screening Program.

The Hemoglobinopathy Learning Collaborative grantees are developing strategies that will result in more coordinated and appropriate care in order that individuals with sickle cell disease experience fewer complications, acute care visits, and hospitalizations; enhanced quality of life; and more compassionate and respectful treatment from the health care system. Processes are also being developed to ensure that individuals screened for sickle cell disease and sickle cell trait receive genetic counseling, education and appropriate follow-up care for their condition. The aims of the collaborative are aligned with the national quality strategy of the Triple Aim—better care, better health, and lower overall health care costs [18]. The strategies and approaches developed and tested by the teams will be disseminated to the broader sickle cell community for use in the treatment and management of individuals with sickle cell disease.

The Hemoglobinopathy Learning Collaborative’s approach is based on the structure of the Breakthrough Series Learning Collaborative [19–21], a model championed by the Institute for Healthcare Improvement that brings together health care organizations that share a commitment to making major, rapid changes in order to produce breakthrough improvements in quality. Using a process known as the Model for Improvement [22], the teams develop ideas for changes, test small-scale changes using Plan-Do-Study-Act (PDSA) cycles, and measure to determine if the changes are leading to improvement. This method can quickly identify promising ideas and adapt and develop them to into robust, reliable standard processes [2].

There are 15 improvement teams working on quality improvement projects focused on improving acute care management, provision of recommended care, transition, self-management, provider education, and screening, counseling, and education for individuals with SCD and SCT. The 5 articles in this special series span these major content areas, from improving outcomes in the emergency department using standardized order sets to assessing the readiness of adolescents to transition to adult care, to using health information technology to improve care coordination, to developing a home pain management plan, and to using patient navigators to help coordinate care and resources. The series begins with the article by Treadwell et al in this issue and will continue for the next several months. The WISCH teams will serve as leaders for sustainable and positive change for treatment of individuals with sickle cell disease and sickle cell trait in the United States. Their work is an important step towards transforming care for people with sickle cell disease, so that each person with sickle cell disease will receive the highest quality of care throughout their lifespan.

Corresponding author: Suzette Oyeku, MD, MPH, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 3444 Kossuth Ave, 1st Fl, Bronx, NY 10467, [email protected].

From the National Initiative for Children’s Healthcare Quality, Boston, MA.

This month JCOM launches a series calling attention to 5 teams working to improve care for individuals with sickle cell disease and sickle cell trait in the Hemoglobinopathy Learning Collaborative (—Ed.)

Sickle cell disease affects close to 100,000 people in United States [1]. This condition is characterized by chronic anemia and unpredictable pain episodes beginning in early childhood and leading to changes in functioning, diminished health-related quality of life, end-organ damage, increased health care use, and in some cases early mortality [2–5]. Sickle cell disease is identified through universal newborn screening [6] and is found in one in 2474 newborn Americans [7], with Americans of African ancestry most frequently affected. It is estimated that over 2 million Americans are genetic carriers of the sickle cell gene.

Although there have been major advancements in sickle cell care within the past several decades, there still exist significant variations in care and mortality [8–14]. Ongoing strategies to improve patient access to efficacious treatments are essential to improve outcomes for individuals with sickle cell disease.

Recognizing the compelling need for a focused national effort to improve care for this population and the relative lack of private resources committed to it [15], Congress established 2 federal programs to enhance newborn screening and improve follow-up and care and outcomes for this population: the Sickle Cell Disease Newborn Screening Program in 2002 [16] and the Sickle Cell Disease Treatment Demonstration Program in 2004 [17]. The programs are funded by the Health Resources and Services Administration and administered by the National Initiative for Children’s Healthcare Quality (NICHQ)’s Working to Improve Sickle Cell Healthcare (WISCH) program [2]. NICHQ became the coordinating center for the programs in 2011 and 2010, respectively. Diverse grantees are now working together in a Hemoglobinopathy Learning Collaborative, coordinated and facilitated by NICHQ and its partners Boston Medical Center and the Sickle Cell Disease Association of America. The current rounds of funding continue through 2014 for the Sickle Cell Disease Treatment Demonstration Program and 2015 for the Sickle Cell Disease Newborn Screening Program.

The Hemoglobinopathy Learning Collaborative grantees are developing strategies that will result in more coordinated and appropriate care in order that individuals with sickle cell disease experience fewer complications, acute care visits, and hospitalizations; enhanced quality of life; and more compassionate and respectful treatment from the health care system. Processes are also being developed to ensure that individuals screened for sickle cell disease and sickle cell trait receive genetic counseling, education and appropriate follow-up care for their condition. The aims of the collaborative are aligned with the national quality strategy of the Triple Aim—better care, better health, and lower overall health care costs [18]. The strategies and approaches developed and tested by the teams will be disseminated to the broader sickle cell community for use in the treatment and management of individuals with sickle cell disease.

The Hemoglobinopathy Learning Collaborative’s approach is based on the structure of the Breakthrough Series Learning Collaborative [19–21], a model championed by the Institute for Healthcare Improvement that brings together health care organizations that share a commitment to making major, rapid changes in order to produce breakthrough improvements in quality. Using a process known as the Model for Improvement [22], the teams develop ideas for changes, test small-scale changes using Plan-Do-Study-Act (PDSA) cycles, and measure to determine if the changes are leading to improvement. This method can quickly identify promising ideas and adapt and develop them to into robust, reliable standard processes [2].

There are 15 improvement teams working on quality improvement projects focused on improving acute care management, provision of recommended care, transition, self-management, provider education, and screening, counseling, and education for individuals with SCD and SCT. The 5 articles in this special series span these major content areas, from improving outcomes in the emergency department using standardized order sets to assessing the readiness of adolescents to transition to adult care, to using health information technology to improve care coordination, to developing a home pain management plan, and to using patient navigators to help coordinate care and resources. The series begins with the article by Treadwell et al in this issue and will continue for the next several months. The WISCH teams will serve as leaders for sustainable and positive change for treatment of individuals with sickle cell disease and sickle cell trait in the United States. Their work is an important step towards transforming care for people with sickle cell disease, so that each person with sickle cell disease will receive the highest quality of care throughout their lifespan.

Corresponding author: Suzette Oyeku, MD, MPH, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 3444 Kossuth Ave, 1st Fl, Bronx, NY 10467, [email protected].

From the National Initiative for Children’s Healthcare Quality, Boston, MA.

This month JCOM launches a series calling attention to 5 teams working to improve care for individuals with sickle cell disease and sickle cell trait in the Hemoglobinopathy Learning Collaborative (—Ed.)

Sickle cell disease affects close to 100,000 people in United States [1]. This condition is characterized by chronic anemia and unpredictable pain episodes beginning in early childhood and leading to changes in functioning, diminished health-related quality of life, end-organ damage, increased health care use, and in some cases early mortality [2–5]. Sickle cell disease is identified through universal newborn screening [6] and is found in one in 2474 newborn Americans [7], with Americans of African ancestry most frequently affected. It is estimated that over 2 million Americans are genetic carriers of the sickle cell gene.

Although there have been major advancements in sickle cell care within the past several decades, there still exist significant variations in care and mortality [8–14]. Ongoing strategies to improve patient access to efficacious treatments are essential to improve outcomes for individuals with sickle cell disease.

Recognizing the compelling need for a focused national effort to improve care for this population and the relative lack of private resources committed to it [15], Congress established 2 federal programs to enhance newborn screening and improve follow-up and care and outcomes for this population: the Sickle Cell Disease Newborn Screening Program in 2002 [16] and the Sickle Cell Disease Treatment Demonstration Program in 2004 [17]. The programs are funded by the Health Resources and Services Administration and administered by the National Initiative for Children’s Healthcare Quality (NICHQ)’s Working to Improve Sickle Cell Healthcare (WISCH) program [2]. NICHQ became the coordinating center for the programs in 2011 and 2010, respectively. Diverse grantees are now working together in a Hemoglobinopathy Learning Collaborative, coordinated and facilitated by NICHQ and its partners Boston Medical Center and the Sickle Cell Disease Association of America. The current rounds of funding continue through 2014 for the Sickle Cell Disease Treatment Demonstration Program and 2015 for the Sickle Cell Disease Newborn Screening Program.

The Hemoglobinopathy Learning Collaborative grantees are developing strategies that will result in more coordinated and appropriate care in order that individuals with sickle cell disease experience fewer complications, acute care visits, and hospitalizations; enhanced quality of life; and more compassionate and respectful treatment from the health care system. Processes are also being developed to ensure that individuals screened for sickle cell disease and sickle cell trait receive genetic counseling, education and appropriate follow-up care for their condition. The aims of the collaborative are aligned with the national quality strategy of the Triple Aim—better care, better health, and lower overall health care costs [18]. The strategies and approaches developed and tested by the teams will be disseminated to the broader sickle cell community for use in the treatment and management of individuals with sickle cell disease.

The Hemoglobinopathy Learning Collaborative’s approach is based on the structure of the Breakthrough Series Learning Collaborative [19–21], a model championed by the Institute for Healthcare Improvement that brings together health care organizations that share a commitment to making major, rapid changes in order to produce breakthrough improvements in quality. Using a process known as the Model for Improvement [22], the teams develop ideas for changes, test small-scale changes using Plan-Do-Study-Act (PDSA) cycles, and measure to determine if the changes are leading to improvement. This method can quickly identify promising ideas and adapt and develop them to into robust, reliable standard processes [2].

There are 15 improvement teams working on quality improvement projects focused on improving acute care management, provision of recommended care, transition, self-management, provider education, and screening, counseling, and education for individuals with SCD and SCT. The 5 articles in this special series span these major content areas, from improving outcomes in the emergency department using standardized order sets to assessing the readiness of adolescents to transition to adult care, to using health information technology to improve care coordination, to developing a home pain management plan, and to using patient navigators to help coordinate care and resources. The series begins with the article by Treadwell et al in this issue and will continue for the next several months. The WISCH teams will serve as leaders for sustainable and positive change for treatment of individuals with sickle cell disease and sickle cell trait in the United States. Their work is an important step towards transforming care for people with sickle cell disease, so that each person with sickle cell disease will receive the highest quality of care throughout their lifespan.

Corresponding author: Suzette Oyeku, MD, MPH, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 3444 Kossuth Ave, 1st Fl, Bronx, NY 10467, [email protected].

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.