Posts Tagged ‘Medical Ethics’

H.I.V. treatment advances, but what are the implications of terminating research early?

Wednesday, May 18th, 2011

Scientific Method; image from: scifiles.larc.nasa.gov

Last week, I read some exciting news about H.I.V. treatment and transmission. A New York Times article reported that a large clinical trial found that “[p]eople infected with the virus that causes AIDS are far less likely to infect their sexual partners if they are put on treatment immediately instead of waiting until their immune systems begin to deteriorate…” The study found that “[p]atients with H.I.V. were 96 percent less likely to pass on the infection if they were taking antiretroviral drugs…” These findings are overwhelmingly positive and the implication for public health is huge.

The study details are fascinating, particularly in regards to the results. For example:

The $73 million trial, known as HPTN 052, involved 1,763 couples in 13 cities on four continents. One member of each couple was infected with H.I.V.; the other was not. In half the couples, chosen at random, the infected partner was put on antiretroviral drugs as soon as he or she tested positive for the virus.

In the other half, the infected person started treatment only when his or her CD4 count — a measure of the immune system’s strength — dropped below 250 per cubic millimeter.

In 28 of the couples, the uninfected person became infected with the partner’s strain of the virus. Twenty-seven of those 28 infections took place in couples in which the partner who was infected first was not yet getting treatment.

What I found most interesting, however, was that the study was not completed. The reported findings were the preliminary results from the clinical trials. In fact, the article explained that “[t]he data was so convincing that the trial, scheduled to last until 2015, is effectively being ended early.”

The way these results were discovered and released during the course of the study was what intrigued me. Here’s how the study data was described:

“[U]nblinded” to an independent safety review panel, which is standard procedure in clinical trials. When the panel realized how much protection early treatment afforded, it recommended that drug regimens be offered to all participants. Although participants will still be followed, the trial is effectively over because it will no longer be a comparison between two groups on different regimens.

This means that the clinical trial was stopped before reaching completion so that all of the participating couples could receive treatment.

The implications of ending this trial short are complicated. For the participants, the decision can be nothing but positive since it may provide the study participants with the opportunity to receive treatment that could hopefully lead to a dramatically decreased likelihood of infection with a potentially deadly disease. For many others around the world who have a partner with H.I.V., the implications are likewise a boon for public health. The release of these early results may impact treatment of H.I.V. infected individuals around the world who may now be able to protect their partners from infection. However, the end of this study is not as clear-cut in terms of research and ethical implications as it might seem.

I originally became aware of the idea that clinical studies are sometimes cut short in the mid 1990s. My father, an occupational health doctor who died in 1999, was involved in the CARET studies during the 1990s. This large-scale double blind study was looking at whether beta-carotene and retinyl palmitate would be able to prevent lung cancer in heavy smokers and workers who had been exposed to asbestos.  However, the study was ended prematurely based on interim results that suggested an adverse affect on the study participants. Since I was only a high school student at the time that the trial was ended, I did not know many of the details at the time. I understood the basic idea that if a medical research study was causing harm to the participants, that it must be ended. When I read the recent news about the H.I.V. treatment study, it prompted me to try to learn more about how and when clinical studies are interrupted.

There was an article published called “Stopping the active intervention: CARET” that I found enlightening about how and why the CARET studies were ended.  The article provides an overview that I found helpful in thinking about the current H.I.V. study:

The optimal design of a randomized clinical intervention trial, where the outcome is a disease endpoint, includes a set of criteria for stopping the active intervention before planned. These criteria, called “stopping rules,” guide the review of findings by key study scientists and an independent set of reviewers. If the pattern of outcome, effect or harm, is large enough to be attributed to the intervention, the trial is halted, regardless of the planned completion date or the readiness of staff to end the trial.

While in the H.I.V. study, the impact was positive, rather than negative as in the CARET study, the procedure seems to be similar. A procedure in the study allowed for data to be unblinded and examined by an independent panel which then recommended that the trial be stopped early.

However, this does present two potential problems. One is that the study, scientifically speaking, did not reach its full conclusions. It may not provide as much evidence of implications as it might have if it had continued or if the study population had been larger. For example, the New York Times article mentioned the following:

Although the trial was relatively large, there are some limitations on interpreting the data.

More than 90 percent of the couples in the trial, who lived in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe, were heterosexual.

“We would have liked to have a substantial number of men as potential study subjects, but they just weren’t interested,” Dr. Cohen said.

Although common sense suggests the results would be similar in the contexts of homosexual sex and sex between people who are not couples, strictly speaking, the results apply only to the type of people studied, Dr. Fauci said.

Another implication is that the results may not be as scientifically accurate if the trials are stopped early.  A study published in JAMA entitled “Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects: Systematic Review and Meta-regression Analysis” explains:

Although randomized controlled trials (RCTs) generally provide credible evidence of treatment effects, multiple problems may emerge when investigators terminate a trial earlier than planned, especially when the decision to terminate the trial is based on the finding of an apparently beneficial treatment effect. Bias may arise because large random fluctuations of the estimated treatment effect can occur, particularly early in the progress of a trial. When investigators stop a trial based on an apparently beneficial treatment effect, their results may therefore provide misleading estimates of the benefit. Statistical modeling suggests that RCTs stopped early for benefit (truncated RCTs) will systematically overestimate treatment effects, and empirical data demonstrate that truncated RCTs often show implausibly large treatment effects.

(internal footnotes omitted)

So, perhaps, if the trial were continued, the results would not have been as overwhelmingly positive. Perhaps the percentage of partners infected in the two groups would not have been as widely divergent. But perhaps they would – and would you want to gamble with someone’s life?

Have you ever been involved in a clinical research study that has been ended early? Was it for positive or negative results? What should be done to maximize public health and safety while still providing the benefits of full blind research studies?

 

Confusion with Advanced Directives: Palliative Care, End-of-Life & Hospice Care

Tuesday, December 21st, 2010

In a previous blog, I raised the issue of “Advanced Directives” and how, according to a Medscape physician survey, physicians do not always honor these legal documents.  One of the “excuses” cited the definition of futility in treating a terminal medical condition, arguing for palliative care as opposed to withdrawal of care.  Obviously, confusion exists amongst these providers as to what constitutes comfort care versus unnecessary prolongation of life and/or exposure to unnecessary procedures in a patient with a terminal condition.

Palliative, End-of-Life and Hospice Care

Palliative care is essentially comfort care.  To “palliate” means to “ease” or “make less severe” – therefore, medical care that is designed to palliate symptoms of a particular disease is care designed to ease or lessen the severity of symptoms associated with that disease.  It can be in an acute condition, a chronic condition or even a terminal condition depending on the stage of the illness.  Some of the symptoms often palliated are nausea and vomiting (chemotherapy, cirrhosis), anorexia (cancers, AIDS), pain (rheumatoid arthritis, cancers), shortness of breath (COPD/emphysema, interstitial lung disease), dizziness (Meniere’s disease, multiple sclerosis), incontinence (spinal cord injuries, stroke), constipation (inflammatory bowel disease, chronic pain syndromes), and many others.  There are various treatments available for the treatment and/or management of these symptoms, but they are not necessarily curative of the underlying condition.  Some chronic conditions, like Rheumatoid Arthritis, are manageable but not necessarily curable, so the treatment rendered is to palliate/lessen the symptoms and hopefully put the auto-immune disorder into remission for a period of time.  Rheumatoid Arthritis, however, is NOT a terminal condition; patients usually die of complications or other co-morbidities.  Palliative care can also incorporate a variety of specialties with overall coordination of care that involves communication with the family, spirituality and emotional support.  Palliative care is a critical component of end-of-life and Hospice care.

End-of-Life care is a well-coordinated approach to end-of-life issues when a condition is deemed terminal, such as incurable metastatic cancer, end-stage multiple sclerosis or even liver cirrhosis when organ transplant is not an option.  Life expectancy can vary widely, with physician guestimates being greater than 6 months (as much as one year or more).  End-of-life care typically incorporates palliative care to ease the symptoms of the disease process as well as counseling services, emotional support and even spiritual support.

Hospice care is end-of-life care, incorporating palliative care, reserved for the last 6 months of life or less.  Care is shifted from curative therapies to pain management and ease of other symptoms of illness.  There are many Hospice programs that offer services in a variety of locations, all of which is dependent on the patient’s and the patients’ family’s wishes. They can be rendered at home, in a nursing home, in the hospital or in a dedicated Hospice facility.  Services provided by these organizations can even include basic housekeeping, personal hygiene care, grocery shopping, and even companionship in addition to the palliative medical therapies.

Where do advanced directives come into play?

Advanced directives can affect every one of these aspects of care.  They reflect the patient’s or the patient’s medical power of attorney’s wishes regarding palliative care modalities, end-of-life care and Hospice care.

About.com’s website on palliative care offers a great example of palliative care that transitions to end-of-life and at-home Hospice care for “Aunt Tilly”.

A patriarch of the family has essentially been healthy his entire life, shoveling  snow and cutting grass into his 85th year of life.  Things shift during the 86th year, and he develops congestive heart failure which has triggered multiple falls and syncopal episodes, presumably from hypoxemia.  There are several hospitalizations to evaluate his condition with institution of multiple medical therapies/drugs to stabilize his condition.  Unfortunately, his heart is weak, and ultimately his kidneys begin to fail.  No advanced directives had ever been discussed, as with many people of his generation; fortunately, he remained of sound mind.  At first, everything was a whirlwind……medication infusions to prevent irregular heart rhythms, blood transfusions to address his anemia since the kidneys were no longer working properly to stimulate the bone marrow to make more red blood cells, and finally, dialysis???  Well, if the kidneys are not working very well, not filtering the blood to produce urine and not stimulating the bone marrow to produce RBCs, we have to fix this, right?  What was not mentioned was that blood transfusions have to be given with intravenous fluids, which then worsen the fluid overload and congestive heart failure making it even more difficult for the poor man to breathe.  Higher and higher amounts of oxygen are needed to keep him comfortable, while his body is swelling up with fluids.  So, STOP THE MADNESS!  This family patriarch, after being informed of the complicated nature of his essentially end-stage condition, opted to forego hemodialysis; he did not want to be hooked-up to a machine for 3 hours a day, 3 days a week, just to filter his blood in an attempt to garner perhaps 6 more months of life; that kind of life had no quality to it in his mind.  In addition, since the blood transfusions would only worsen his breathing, he refused any more blood.  He wanted to be kept comfortable with pain medications and oxygen which was done in the hospital; he did not want to be shocked (defibrillated) or resuscitated in any way.  Comfort measures were provided in the hospital where he was given a large, private room, and he passed away peacefully within 3 days; there were no restrictions on family visitation, and he was surrounded by those dearest to him.  A chaplain was available within minutes of his death to comfort the family and offer prayer to ease everyone else’s suffering and loss; this patriarch was already at peace and without pain.

In this particular example, it was beneficial that my family member was of sound mind to make his own decisions at the end of life with regard to blood transfusions and hemodialysis.  It would have otherwise been very difficult for the family to come to some kind of consensus.  It was also better, in this case, that he remain in the hospital since his wife was still living and would have to return to their home alone following his death; having her live in the house in which her husband of 67 years had died would have been too much for her to bear.  This emphasizes the importance decision-making while one is of sound mind.  Cancers can spread to the brain; toxic metabolites that accumulate when vital organs fail can render a patient confused or even comatose; acute strokes can also affect one’s cognitive capabilities, not to mention other organ systems (breathing, toileting, swallowing, etc.).

Advanced directives can be as precise or as vague as one desires.  It seems to me that the more detailed the directive, the less chance one encounters of a physician or care provider ignoring the directive or “interpreting” the directive in a way that confuses loved ones, exposing the patient to unnecessary procedures and/or life-extending treatments.

Have you ever had to deal with any of these issues – advanced directives, palliative care, end-of-life care or hospice care? What has your experience been? Do you have any suggestions that might be helpful to others, who may be faced with similar issues?

More on this topic soon: What constitutes a terminal condition?

Related Posts:

Advanced Directives: The Right to Die With Dignity. Does the Medical Profession Honor Them?

Making Your Wishes Known at the End of Life (NY Times article by Dr. Pauline W. Chen )

Image from mylocalhealthguide.com


Advanced Directives: The Right to Die with Dignity. Does the Medical Profession Honor Them?

Friday, December 3rd, 2010

Anyone who has presented to a hospital with some type of ailment in the last 10 years or so has been asked about advanced directives, a living will and/ or medical power of attorney. What are these things?  What do they do?  Better yet, you may ask: what are they intended to do?

Advanced directives are legal documents prepared while an individual is of sound mind that indicates his or her wishes with regard to medical decisions to be made in the event that the same individual becomes incoherent, comatose, or unable to make decisions for themselves.

These directives are intended to instruct the care-providers with regard to various medical interventions should their condition warrant intervention. These can be as “simple” as resuscitation orders (being “coded,” “shocked,” being intubated and/or placed on a mechanical ventilator), or they can be more complex such as gastric feeding tubes if one cannot eat by mouth, dialysis should one’s kidneys fail (even temporarily), intravenous fluids or intravenous nutrition, blood transfusions, surgical procedures if the condition is deemed terminal, pacemaker/defibrillator placement, and many other form of possible medical intervention.  A living will is a form of advanced directive that is less precise, but it is a legal document indicating a patient’s wishes with regard to end-of-life or terminal-condition medical care without assigning a medical power of attorney. A medical power of attorney legally identifies an individual, who is intimately trusted by the patient to make appropriate decisions with regard to medical care in accordance with the patient’s wishes should the patient become incapable of making those decisions. The American Academy of Family Physicians offers good information with regard to these topics.

How well does the medical community deal with these issues?

This is all well and good from the patient’s perspective, but where do the physicians and other medical care providers fall in line with such legal documents and end-of-life ethical decision-making?  According to an electronic survey of 10,000 physicians in 2009 by Medscape on medical ethics, a physician’s personal bias and personal beliefs played a role in their approach to end-of-life care. A second article from Medscape dealt specifically with end-of-life issues.

When queried as to physicians recommending or administering life-sustaining therapy, when one judged it as futile (otherwise terminal condition), 23.6% of the respondants (~5,300) said “yes”; 37% said “no”; 39.4% stated that their decision was situational. The second end-of-life ethical dilemma involved whether the physician would withdraw life-sustaining care in accordance with family wishes even if the physician thought it was premature; the results showed that 54.5% would NOT withdraw care while 16.3% would withdraw care, leaving 29.2% deciding upon the actual situation. Let’s not overlook that astounding number – only 16.3% said they would follow the patient/family’s wish to withdraw care!

Various rationales were cited as to why these physician-respondents held such opinions. Some questioned the motives of the patient’s family members, while others noted fear of litigation for providing medical interventions.  The very definition of “futile” took on both curative and palliative connotations. The legitimacy of advanced directives were also questioned since these can become viewed as stagnant, especially if created 5 or 10 years earlier while the patient was in a different mindset. Keep in mind, people do change their mind, as do their perspectives with age, experience and wisdom. Likewise, advanced directives need to be changed, modified or simply updated periodically to reflect such changes.

The Terri Schiavo lesson (if there was one)

The Terri Schiavo story brought the whole end-of-life ethical decision-making into the limelight in 2005. This very sad story was in the headlines every day as legal maneuvering played out on national television. People were divided on “who was right,” and they will always be divided. These decisions are personal. They are difficult to share and discuss with family members, let alone physicians, who are admitting patients for the first time. In Maryland, physician assistants have been required to acquire continuing education hours in end-of-life care on a yearly basis for the last 10 years! This is a critical step in understanding the terminal stages of disease as well as the psychologic impact it can have on patients and their families.  Being comfortable with the discussion of death and dying, and doing so with dignity, is a key component in the management of end-of-life decision-making.

A Personal Experience

On a personal note, as a practicing physician’s assistant, I have been involved in end-of-life decisions with several family members as well as patients presenting to the ER in my 13-year Emergency Medicine career. The family members I have encountered have run the gamut from cancer-related deaths to brain hemorrhages to congestive heart failure leading to kidney failure.

One memorable, personal, family incident that sticks involved a relative, who had been living with a stroke, chronic lymphocytic leukemia followed by the development of large cell lymphoma. The two different courses of chemotherapy for the lymphoma resulted in damage to his heart, causing episodes of ventricular tachycardia (a life-threatening heart rhythm); however, the lymphoma had returned, and he couldn’t eat due to illness.  His options with regard to the cancer were extremely limited with an extremely poor prognosis, but the cardiologist wanted to insert a defibrillator in case the ventricular tachycardia re-occurred; the defibrillator would deliver an internal shock to the heart to return it to a normal rhythm and prevent death. Well, what is worse in this case – dying from a painless, silent heart dysrhythmia or suffering from malnutrition and systemic pain from the cancer that was everywhere in his body?  This situation required forcing both the oncologist and cardiologist to meet with my relative and with the our family to discuss each option and the prognosis. My relative decided he wanted to go home as soon as possible without the defibrillator; he died within a few days, silently and by all observations – peacefully. That was his choice, and it was honored after convincing his caregivers to abide by his decision.

It’s not Marcus Welby who will be taking care of you

Our current medical system is so over-burdened with patients at every level of care that the days of the old-fashioned family doctor who still admits his or her own patients and “rounds” on them every day (in addition to fulfilling their office obligations) are long-gone. Some patients are admitted to “hospitalists” (whom they have never met before) while others get admitted to whomever might be on-call in any variety of specialties (whom they also have never met before). Specialty medicine is just that……they focus on their particular specialty (as in the case of my relative). So, having a heart-to-heart discussion with your trusted family physician regarding your beliefs about end-of-life issues many (if not most) times never translates to the acute medical condition that lands you in the hospital. Even nursing home patients with DNR (do not resuscitate) forms can be ignored if they are not properly completed or the patient is not wearing the matching bracelet!

It seems that not only do patients need to be educated about the benefits of an advanced directives, living will and power of attorney, but physicians also need to be educated regarding compassionate, end-of-life and terminal care involving the whole being, such that they can communicate with family members, accept advanced directives and offer solutions to the dilemmas often faced by confused and emotionally drained family members faced with such situations.

Just as there should be dignity with life, there should be dignity with death.  It is the responsibility of both patients and providers to ensure this aspect of the human condition at whatever stage of a patient’s illness.

Have YOU ever been faced with such a situation?

Have you ever been faced with a situation where you were asked to make care decisions without an advanced directive? Have you ever found yourself in a situation where there was an advanced directive but the physician would not abide by it? Do you believe that it is a patient’s right to determine how they want to die and what medical interventions should be withheld under certain circumstances? How did YOU deal with such a situation?

Photo from enrichmentjournal.ag.org