Pharmacogenetic testing's promise, problems, and pitfalls

 - Kenny Lin, MD, MPH

In 2019, Dr. Carl Bryce wrote a Diagnostic Tests review in American Family Physician about the allopurinol hypersensitivity assay, "a blood test to detect the presence of a human leukocyte antigen B [HLA-B] genetic variant that increases the risk of life-threatening, severe cutaneous reactions in patients taking allopurinol." According to this article and a rapid evidence review of gout, testing was recommended for Korean adults with stage 3 or higher chronic kidney disease and all adults of Han Chinese or Thai descent, who have a higher frequency of the variant, prior to initiating allopurinol. In 2020, the American College of Rheumatology (ACR) simplified and broadened this testing recommendation to "people of Southeast Asian and African American descent."

Though pharmacogenetic testing holds promise for improving clinical decision-making, a recent JAMA Viewpoint contended that race-based testing recommendations are problematic. Even a racially homogenous European country such as Switzerland exhibits wide genetic diversity in the frequency of the HLA-B*58:01 allele, with one city (Basel) actually having a higher frequency than the U.S. African American population. Further examination of the ACR's race-based guidance reveals additional complexities and contradictions:

The ACR guideline cites Han Chinese, Korean, and Thai as examples of Southeast Asian descent, even though China and Korea are not typically considered Southeast Asian countries. The guideline then states that screening is cost-effective in Asian populations generally. However, Japan is in Asia, but the allele frequency of HLA-B*5801 in Japan is even lower than that of White individuals in the US, who are not recommended for screening. In addition, the recommendation to screen all African American patients in the US before prescribing allopurinol belies wide-ranging HLA-B*5801 variation across Africa, where reported HLA-B*5801 frequencies, based on small sample sizes, range from 1% (comparable with White individuals in the US) to 10% (comparable with Thailand).

In an AFP editorial published online last month, Dr. Bonzo Reddick took aim at a related issue: the use of diagnostic and clinical prediction tools that, like pharmacogenetic tests, incorrectly utilize race as a proxy for genetic differences. These include the atherosclerotic cardiovascular disease (ASCVD) Pooled Cohort risk calculator, equations for glomerular filtration rate (GFR), a calculator for predicting the likelihood of a successful vaginal birth after cesarean delivery, and pulmonary function testing "correction factors" for Black and Asian patients.

Recognizing that "claims about pharmacogenetic testing ... are inconsistently supported by scientific evidence, and most tests have not been examined by the U.S. Food and Drug Administration [FDA]," Drs. Wendy Rubinstein and Michael Pacanowski shared the FDA's perspective on what clinicians need to know in the July issue of AFP. In a table of selected pharmacogenetic associations, they summarized known and potential gene-drug interactions and recommendations for clinical practice, when applicable. In a Diagnostic Tests review in the same issue, Dr. Natasha Pyzocha evaluated GeneSight Psychotropic, an expensive test panel that analyses 12 genes with possible interactions with 57 neuropsychiatric medications. Dr. Pyzocha concluded that while this test may help patients who have had multiple unsuccessful trials of therapy, "because only a small population of patients are expected to have genetic phenotypes that would necessitate medication changes, ... routine genetic testing is not recommended," and "choosing antidepressants based on health history and symptoms should still be the standard initial approach."

Should the FDA have approved aducanumab?

- Jennifer Middleton, MD, MPH

The US Food and Drug Administration (FDA) recently approved  aducanumab (Aduhelm), "a first-of-its-kind treatment....that targets the fundamental pathophysiology" of Alzheimer's disease. Pharmacologic treatment options for Alzheimer's disease have previously only targeted symptoms, but aducanumab purports to attack the amyloid plaques "that result in loss of neurons and their connections." Aducanumab's approval, however, has been met with criticism from both the medical community and members of the FDA themselves.

The FDA approved aducanumab via its accelerated approval pathway, intended for "drugs for serious conditions that fill an unmet medical need." The accelerated approval pathway permits drug makers to present less rigorous (and less time consuming) outcomes than the traditional approval process:

A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).

The two phase III trials that aducanumab's manufacturers presented to the FDA had identical study designs; each enrolled adults worldwide aged 50-85 with symptoms consistent with early Alzheimer's disease and randomized them into 3 groups: placebo, low-dose aducanumab, and high-dose aducanumab (all administered every 4 weeks intravenously). Their primary endpoint was the Clinical Dementia Rating - Sum of Boxes (CDR-SB), administered at participant enrollment and again after 78 weeks of treatment.  Neither study found benefit for low-dose aducanumab; one study's results suggested potential for high-dose aducanumab, while the other study did not.

Perhaps not unsurprisingly, 10 of the 11 FDA advisory committee members voted against aducanumab's approval in November of 2020 after reviewing the results of these 2 studies. Yet on June 7, 2021, the FDA approved aducanumab, citing trial data demonstrating that "[p]atients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque." It's notable that the FDA justified its decision using one of the trials' secondary outcome measures and not the primary outcome measure, CDR-SB, that had inconsistent results. Three physicians resigned from the FDA advisory committee in protest, including Dr. Aaron Kesselheim, who has since publicly aired his concerns regarding the drug's questionable safety, unproven efficacy, monitoring requirements, and steep price tag ($56,000/year). Allegations of improper communications between aducanumab's manufacturers and the FDA have also emerged, casting more doubt on the propriety of aducanumab's approval.

Patient advocacy groups are cheering aducanumab's approval, though, and understandably so; the devastation Alzheimer's disease wreaks on patients and families is profound, and the potential to ameliorate that suffering with a completely new drug is tantalizing. The FDA is requiring aducanumab's manufacturers to continue gathering data regarding its safety and efficacy, so time will tell whether the FDA's approval decision will prove to be a rash or sound one.

You can read more about Alzheimer's disease, and other dementia disorders, at the AFP By Topic on Dementia, which includes this 2017 AFP overview of "Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms." 

Which U.S. hospitals are providing Right Care to their communities?

 - Kenny Lin, MD, MPH

The Lown Institute, which has partnered with AFP since 2018 on a series of Right Care articles addressing clinical scenarios of overuse and underuse in primary care, recently released the second edition of its Hospitals Index. Unlike traditional metrics that are primarily based on a hospital's revenue and reputation, the Lown Institute Hospitals Index ranks U.S. hospitals by equity, value, and outcomes nationally and by state. This year, Lown produced separate rankings of hospitals by overuse of low-value tests and procedures, racial inclusivity, and community benefit.

A key finding of this year's community benefit ranking is that more than 7 in 10 private nonprofit hospitals spend less on charity care and community investment than they receive in tax breaks (what Lown terms a "fair share deficit"). These hospitals' collective fair share deficit was $17 billion, with the bottom ten hospitals representing $1.8 billion of that national total. Although pre-2010 data are not available for comparison, the size of this deficit seems to suggest that the Affordable Care Act's requirement for nonprofit hospitals to conduct community health needs assessments (CHNAs) every 3 years hasn't led to greater investments in community health. However, New York State's Prevention Agenda legislatively required nonprofit hospitals to collaborate with local health departments on CHNAs starting in 2013. A recent analysis of IRS data found that compared to a control group of hospitals in the other 49 states and District of Columbia, New York hospitals increased their mean spending on population health improvement by $393,000-$786,000.

More information on the Lown Institute Hospitals Index methodology is available in a JAMA Network Open article and in recorded webinars and explanatory videos. U.S. News & World Report has announced that its 2021-22 Best Hospitals ranking will incorporate Lown's metric for overuse of spinal fusion. In an editorial in the May 15 issue of AFP, Drs. Alan Roth and Andy Lazris pointed out that a silver lining of the COVID-19 pandemic is that many patients avoided unnecessary spinal fusions and other interventions of questionable benefit, such as electrocardiograms in asymptomatic, low-risk adults. Whether these gains in Choosing Wisely will be preserved post-pandemic is unclear. Finally, in a June 15 Lown Right Care article, Drs. Roth and Lazris joined AFP Patient Partners Helen Haskell and John James in highlighting the negative health consequences of poor physician-patient communication.

Discussing COVID-19 vaccine risks with patients

- Jennifer Middleton, MD, MPH

Data continues to emerge regarding the safety of COVID-19 vaccination in pregnant and younger persons. 

When my pregnant sister asked me a few months ago if she should get vaccinated against COVID-19, I didn't hesitate to advise "yes." We now have published data suggesting that vaccination does not alter pregnancy outcomes. Researchers reviewed two-and-a-half months of data from vaccine safety surveillance systems, including over 35,000 pregnant persons, and found rates of preterm birth and miscarriage comparable to established rates pre-pandemic. Given that pregnancy confers a higher risk of COVID-19 complications, it seems reasonable to continue to advise vaccination for pregnant persons while we await more definitive, long-term data. 

Concerns about post-vaccination myocarditis have also been making headlines. A case series published last week examined myocarditis incidence in members of the United States military. 23 male patients were diagnosed with myocarditis after an evaluation for acute chest pain within 12 to 96 hours after receiving a COVID-19 vaccine. Most cases occurred after the 2nd vaccine (and all of the individuals with myocarditis after their 1st vaccine dose had previously diagnosed COVID-19). The US military administered over 3 million doses of COVID-19 vaccines; their described rate of post-vaccination myocarditis is higher than the rate of myocarditis expected in the general population, but the study authors correctly point out that this risk is still quite small compared to the risks of COVID-19 disease:

[I]t is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic. Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients....Prevalence of cardiac injury may be as high as 60%.... Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination. 

Discussing risk with patients in a meaningful way can be challenging. An 2018 FPM article on communicating risk with patients during shared decision making recommends being honest with patients about potential risks, "[u]sing frequencies with the smallest numbers possible (but not “1 in X” [as patients may worry that they'll be that 1])," and avoiding descriptive language (such as "low" or "high" risk). For example, the risk from the above study of myocarditis after COVID-19 vaccination was 19 cases per 100,000 person-years, but the risk of heart problems with COVID-19 infection is as high as 6 in 10. Family physicians are in the perfect position to have these conversations, especially since a recommendation from a trusted physician has historically been the strongest predictor of receipt of any vaccine. 

Even though the US didn't quite meet President Biden's goal of vaccinating 70% of the adult population by July 4, 20 US states and the District of Columbia did meet or surpass that goal. COVID-19 vaccine hesitancy also appears to be decreasing as 2021 progresses, so it's definitely worth continuing to have these conversations with our patients. If you'd like to learn more, the AAFP regularly updates its "COVID-19 Safety and Efficacy Data Overview" website, and this AFP editorial on "Strategies for Addressing and Overcoming Vaccine Hesitancy" contains many useful tips. The blog recently featured this guest post on "Patient-centered discussion of COVID-19 infection and mRNA vaccines" as well.