American College of Physicians: Internal Medicine — Doctors for Adults ®


From bench to bedside: Does race count?

With 'ethnic' drugs on the horizon, controversy grows over how race affects treatment

From the November ACP Observer, copyright 2004 by the American College of Physicians.

By Janet Colwell

Once a week, Donald B. Parks, MD, an internist in North Philadelphia, picks up the phone and calls a 49-year old patient of his who has prostate cancer. The patient, who is black, lost his job and his health insurance several months ago. As a result, he's decided to let the disease run its course, despite Dr. Parks' weekly efforts to convince him to seek intervention.

"I know the cancer could metastasize any time," said Dr. Parks, who is assistant dean of minority affairs at Philadelphia's Temple University School of Medicine. "But he's more afraid of the bill and of being a burden to his family."

For Dr. Parks, who serves a largely black, urban patient population, race factors into treatment only because it is a common denominator in social problems that prevent patients from accessing or continuing care. According to many clinicians, including Dr. Parks, access—not biology—is the No. 1 factor driving racial health care disparities.

According to internist Donald B. Parks, MD, access—not biology—is the No. 1 factor driving higher disease rates and increased healthcare risks for African Americans.

Some pharmaceutical companies, however, may be zeroing in on race as a way to develop and market new drugs. The Massachusetts-based Nitromed Inc., for instance, intends to submit data to the FDA on a heart failure drug it plans to market to African Americans, if the drug is approved.

The company's ethnic pitch would hinge on results from the first clinical trial—the African American Heart Failure Trial (A-HeFT)—to focus exclusively on African-American patients. The trial tested the combination of isosorbide dinitrate and hydralazine that would be marketed as BiDil. (Although results are not yet complete, the trial was terminated because heart failure patients on standard treatment plus placebo had higher mortality than those with standard therapy plus active medicine.)

If approved, BiDil would become the first drug targeted to a specific race, and could jumpstart the flow of other "ethnic" drugs through the pharmaceutical pipeline. At the same time, groups in both the public and private sectors are bringing much more attention to the issue of racial health care disparities and initiating more studies to compare disease progression and treatment response in blacks vs. whites.

No one denies that devastating health care disparities exist, nor that more minority patients should be enrolled in clinical trials. (See "Recruiting minorities into research.") Some experts point out, however, that suggesting that blacks may be biologically different from other patients with heart failure is a dangerous premise. Others worry that "ethnic" drugs may divert attention from the economic and political strategies needed to close the racial divide.

"The downside of [developing ethnic drugs] is that you are possibly stigmatizing members of a racial group by creating the impression that somehow they are racially distinct when it comes to disease," said Ashwini R. Sehgal, MD, an associate professor at Cleveland's Case Western Reserve University who studies racial disparities. "In fact, there is so much overlap among racial groups."

Not in the genes?

Racial health care disparities have been increasingly documented in recent years. (The College's position paper, "Racial and Ethnic Disparities in Health Care," is online. According to the Centers for Disease Control and Prevention, African Americans in particular run a much higher risk than the general population of contracting and dying from HIV/AIDS, heart disease, diabetes, cancer, stroke and hypertension.
(See "Mortality rates: African Americans vs. whites.")

In 2002, the Institute of Medicine reported that blacks' higher death and disease rates were the result of an overall lower-quality level of care. The report, "Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care," singled out socioeconomic differences, including a higher uninsurance rate among non-whites and a greater risk of living in underserved areas, as well as the fact that minorities, even when insured, are more apt to be enrolled in lower-end health plans.

Experts also point to cultural factors that contribute to disparities. People within ethnic groups may share a higher disease risk or respond differently to specific medications because of ingrained cultural habits, such as food preferences that favor high fat content or salt.

Geographic ancestry is another factor that can affect disease risk, with Ashkenazi Jewish women, for example, disproportionately affected by BRCA-1 and BRCA-2 gene mutations. But the idea that race translates into genetic differences that then fuel different rates of disease risk or treatment response is controversial. While experts say race may be a convenient way to categorize research and communicate with patients, racial groups demonstrate a great deal of genetic diversity.

"We use the term 'racial' or 'ethnic' differences even though we know it has no scientific or anthropological meaning," said Beth A. Jones, PhD, MPH, assistant professor of epidemiology and public health at Yale School of Medicine.

That said, Dr. Jones pointed out that targeting racial differences can be a helpful public health tool. In studying cancer, for instance, "We see these very crude designations predict certain outcomes," she said. "They suggest that, imperfect as these designations are, they still capture similarities within groups that can predict health outcomes."

Case study: hypertension

When it comes to black patients, research has focused on racially-based differences in hypertension risk and treatment.

Researchers have targeted race in clinical studies because blacks are more likely than whites to suffer from hypertension and associated heart and renal problems. However, questions persist about whether there is a molecular basis for why certain drugs work better in blacks or whether certain drugs are better suited to high-risk patients, regardless of race.

Conventional wisdom has long held, for instance, that angiotensin converting enzyme (ACE) inhibitors, as well as angiotensin receptor blockers (ARBs) and beta-blockers, do not work as well in blacks as in whites. Why? The general assumption has been that blacks are more likely to suffer from low-renin hypertension while whites tend to have high-renin hypertension.

Because beta-blockers, ACE inhibitors and ARBs block the effects of renin on blood pressure, the thinking goes, they are most effective in patients with high renin. In fact, two ARBs—telmisartan (Micardis) and losartan (Cozaar)—carry warning labels indicating that patient response will be less in blacks than in whites.

But in 2003, the International Society on Hypertension in Blacks began poking holes in that theory with its recommendations for managing high blood pressure in African Americans, published in the March 10, 2003, Archives of Internal Medicine. The authors found blacks' responses to ACE inhibitors and beta-blockers are only general trends and that African Americans still benefit from taking these drugs.

Often, the recommendations stated, adding a diuretic to one of either of these drugs will help black patients reach their blood pressure goals. While the report singled out several factors leading to blacks' higher hypertension rates-including clinical markers such as low birth weight, smoking and obesity—biology was ruled out as a contributing factor.

Another study a year later continued to question the traditional thinking about racially-based hypertension treatment strategies. A meta-analysis published in the March 2004 Hypertension demonstrated that the majority of whites and blacks responded similarly to commonly used antihypertensives.

"Rather than focusing on average differences between blacks and whites, which is what others have done, I looked at the entire distribution of responses," said Case Western's Dr. Sehgal, the study's lead author.

While Dr. Sehgal said the study found small average differences between races in response to standard treatment, the overlap was more significant. Of the patients studied, 95% had similar responses to calcium channel blockers, while 90% had similar responses to diuretics and beta-blockers, and 81% to ACE inhibitors. Instead of using race to tailor treatment, Dr. Sehgal said physicians should consider issues like the cost of a drug, side effects, or whether the patient requires specific cardiac or renal benefits.

That point of view is echoed by clinicians. "Race is less important than disease factors within an individual patient," said Shawna D. Nesbitt, MD, director of the hypertension clinic at Parkland Hospital in Dallas, a county facility where more than 60% of patients are African American.

In fact, Dr. Nesbitt noted, physicians' thinking that specific drugs work differently in one race vs. another may be a detriment to patients. She pointed out that ACE inhibitors and ARBs have been shown to help prevent heart failure and kidney disease, both of which are prevalent in the black community.

"A lot of doctors are reluctant to use these drugs in blacks," said Dr. Nesbitt. "They're preventing the very group that needs these drugs the most from getting the benefit."

The BiDil controversy

According to cardiologist Anne L. Taylor, MD, the study 's chair, the A-HeFT trial, which was co-sponsored by the pharmaceutical Nitromed and the Association of Black Cardiologists, posed these questions: Are the differences in drug responses seen in earlier trials real phenomena? And if they are, might such differences present an opportunity to identify a new treatment strategy?

The trial tested the combination of isosorbide dinitrate and hydralazine in African-American patients with heart failure compared to standard treatment alone, which included ACE inhibitors, ARBs, beta-blockers, diuretics, spironolactone and digitalis.

Leaders of the study say the focus on African Americans was logical, considering the prevalence of hypertension and heart disease in that population and earlier findings that ACE inhibitors and ARBs tend to be less effective in blacks.

However, ongoing efforts to have the drug labeled specifically for use in African Americans have ignited some controversy. (If the drug is approved, Nitromed plans to launch it next year.)

"The pervading message will be that BiDil is for blacks and that a lot of people whom it might help might not get it," said Jonathan Kahn, PhD, JD, assistant professor at Hamlin University School of Law in St. Paul, Minn., who criticized the development of ethnic drugs in the winter 2004 Yale Journal of Health, Policy, Law and Ethics. "The deeper message is that blacks are different at the biological level, because this is a drug that works at the molecular level."

The A-HeFT researchers disagree. Whether or not BiDil's manufacturer markets the drug as "ethnic," they claim the significance of the trial was to open up another treatment option for high-risk patients. The fact that many beneficiaries may be African American stems from the hypothesis that the drug combination makes nitric oxide more available in the body—when previous studies have suggested that blacks are more likely than whites to suffer from nitric oxide deficiency.

"In whites, it may well be that activation of the renin angiotensin system and the sympathetic nervous system is a larger driver [of hypertension], whereas in African Americans, a larger driver may be a deficiency of nitric oxide," said Dr. Taylor, who is professor of medicine at the University of Minnesota Medical School in Minneapolis. "If you then provide an agent that increases the availability of nitric oxide, while also giving a substance that inhibits its clearance [hydralazine], you will improve outcomes. That's what we think was done in A-HeFT."

The consumer press put out an overly simplistic message on trial results, Dr. Taylor said. She pointed out that BiDil was added to standard therapy in the trial. If the drug is approved, physicians might consider it as an additional treatment option for patients—of any race—who fail to respond to first-line treatment. According to Dr. Taylor, the same genetic difference that may show up more often among African American patients may in fact be present in significant numbers of whites or among other ethnic groups as well. She pointed out that there is a genetics sub-study to the A-HeFT trial that will try to identify factors transcending ethnicity that would predict treatment response.

"This drug provides additional survival advantage in patients with heart failure in whom nitric oxide deficiency—we think—is an important reason for the progression of their disease," Dr. Taylor said. "The studies to prove that are still to be done."

Race in the clinic

How do the BiDil controversy and other scientific findings affect clinicians? Practicing physicians say they weigh many factors when tailoring treatments, but that race isn't one of them.

"As long as patients can get into the clinic and access medications and follow up reliably, I don't see a difference in how they respond to care based on their ethnicity or race," said Daniel Cohen, MD, research director and an infectious disease specialist at Fenway Community Health Center in Boston, where the patients, many of whom are HIV-positive, are roughly 75% Caucasian, 15% Hispanic, and 10% African American. "I'm more inclined to look at the patients' insurance status to see if the preferred medication is something that they can afford."

At his clinic in Philadelphia, Dr. Parks said he doesn't rule out the idea that race may play a role in disease outcomes, but it doesn't affect how he runs his practice day-to-day. Access issues loom so large among his patients that ethnic biological differences—if they exist—are a minor consideration.

"We have patients who come to their doctor once every three years, despite notices and phone calls," he explained. "So if they had a lump, it's a bigger lump. Patients come in because they have chest pain, or they're sleeping all the time, or they have headaches. They don't come in and say, 'Listen, I want a physical to check my cholesterol, heart and blood sugar.'"

But even as the issue of ethnic drugs may be about to emerge, research continues to discover important clues that can help guide clinical decisions on how to consider race.

A population-based breast cancer study published in the Sept. 15, 2004, issue of the journal Cancer, for instance, looked at differences in breast cancer between black and white women. It found that African-American women were significantly more likely than whites to have an alteration in the p53 tumor suppressor gene and to have later-stage and larger tumors at the time of diagnosis.

Researchers drew a direct correlation between blacks and the p53 genetic mutation, which is typically acquired during a patient's lifetime and could indicate a higher exposure to carcinogens. Study results also indicated that black women may acquire breast cancer at a younger age and that their tumors may be more aggressive.

The study has important implications for physicians and policymakers, said Yale's Dr. Jones, the study's lead author. "Typically people are more relaxed about screening for women in their 40s," she said, "but in the case of African Americans, it's critical that primary care providers make sure these women are being screened appropriately."

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.


Recruiting minorities into research

Ask researchers why it's tough to recruit minorities into clinical trials, and most will hearken back to the infamous Tuskegee Study, when hundreds of Depression-era black men were deceived into participating in a government-funded study on syphilis and denied access to treatment.

That study (which ended in 1972), as well as numerous trials of prison and mental hospital populations, left lingering distrust in the black community that has thwarted efforts to increase minority participation in clinical research.

"Many people don't know the particulars of what happened, but the bottom line is that they come away saying, 'I'm not going to be a guinea pig,' " said Constance H. Sumner, MSNA, community outreach program coordinator at Fox Chase Cancer Center in Philadelphia.

Tuskegee's legacy adds to other barriers to getting more blacks, Hispanics and other minorities into trials. Researchers say the relatively small number of minority researchers and a lack of education and outreach in minority communities are other major factors.

Statistics on clinical trial participation bear this out. A 2003 National Cancer Institute study of more than 3,000 patients found that African Americans were much less likely than whites to enroll in oncology clinical trials (0.8% vs. 2.8%), and that race was a greater predictor of participation than age, gender or type of insurance.

At Fox Chase, Ms. Sumner, who is African American, organizes free health fairs and health education seminars in predominately black neighborhoods. Only after she has laid that educational groundwork does she start talking about clinical trials and how they can benefit participants.

"Many people still think they will get a sugar pill," she said. "I tell them about informed consent, the treatment options that are out there for cancer and that they will always get at least the standard of care."

One way to increase enrollment is to involve minority groups in setting up studies and interpreting the results. (This was, in fact, the case with the African American Heart Failure Trial that tested the combination of isosorbide dinitrate and hydralazine. Minority physicians were on all key trial committees as well as being investigators.) And helping minorities understand the benefits of participating in studies is key to boosting enrollment, said clinician and researcher Shawna D. Nesbitt, MD, director of the hypertension clinic at Dallas' Parkland Hospital.

At Parkland, which has a mostly minority patient population, doctors take the opportunity to talk to hospitalized patients about research. Dr. Nesbitt's clinic also advertises locally and sends nurses to senior centers to give educational talks.

"We've had a remarkable response to that sort of intervention," Dr. Nesbitt said. To boost minority recruitment in trials, she added, researchers "have to go to where [patients] are comfortable, talk to them in their language and explain clearly how they'll benefit from participating."


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