Should we choose ARBs over ACEis for hypertension?

 - Jennifer Middleton, MD, MPH

Angiotensin-converting enzyme inhibitors (ACEis) have been a first-line medication for hypertension for decades, with well-established mortality and morbidity benefits.  Although newer on the block, angiotensin II receptor blockers (ARBs) have demonstrated many of these same benefits for patients and were included in the Eight Joint National Committee (JNC 8) guideline as another reasonable first-line option for treating hypertension. Initially cost-prohibitive for many patients, most ARBs are now available generic and at similar cost to ACEis, and data has been emerging that their tolerability profile is better than ACEis without sacrificing those all-important patient-oriented outcomes that matter (POEM) benefits. A large cohort study now adds to this evidence base, potentially furthering the case for choosing ARBs over ACEis for patients with hypertension.

The study authors reviewed 8 databases from across the United States, South Korea, and Germany that included over 3 million patients. They identified patients who were started on either an ACEi or an ARB for primary hypertension and noted outcomes related to both cardiovascular disease (CVD) events and adverse medication reactions. They used propensity score models to "adjust for potential confounding and improve balance between the ACE inhibitor and ARB patient cohorts...which included "tens of thousands of measured baseline covariates including: demographics, diagnoses,... [and] comorbidity or risk scores." There was no statistically significant difference between the ACEi and the ARB groups regarding risk of CVD events, but ACEi patients had more adverse medication reactions:

We found no statistically significant difference in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11 for ACE versus ARB [95% CI, 0.95–1.32]), heart failure (hazard ratio, 1.03 [0.87–1.24]), stroke (hazard ratio, 1.07 [0.91–1.27]), or composite cardiovascular events (hazard ratio, 1.06 [0.90–1.25]). Across secondary and safety outcomes, patients on ARBs had significantly lower risk of angioedema, cough, pancreatitis, and GI bleeding.

Specifically, patients receiving ACEis were more likely to experience acute pancreatitis (hazard ratio [HR] 1.32 [95% CI 1.04-1.70]), angioedema (HR 3.31 [95% CI 2.55-4.51]), cough (HR 1.32 [95% CI 1.11-1.59]), and GI bleed (HR 1.18 [95% CI 1.01-1.41]). 

It's important to note that this study was not a randomized controlled trial (RCT); patients were not prospectively divided into randomized groups to rigorously assess for differences between treatments. Its impossible to completely adjust for potential confounders, no matter how rigorous the propensity score models are. Then again, an RCT on this scale would be a sizable undertaking, and cohort study data can still provide useful information. This study is consistent with the findings of an earlier meta-analysis of head-to-head, ACEi versus ARB, RCTs that found no difference in CVD outcomes but increased patient drop-out in the ACEi group, presumably due to side effects. 

This study also would not apply to patients already receiving appropriate treatment for hypertension that is effective and well-tolerated; that is, switching patients to an ARB from an ACEi who are already doing well isn't necessarily warranted. For those patients with a new hypertension diagnosis, though, and/or those patients whose blood pressure control is inadequate and need an additional agent, it may make sense to consider ARBs over ACEis. If you'd like to read more, there's an AFP By Topic on Hypertension which includes sections on Treatment, Improving Practice, and also resources from FPM.  

Measuring and minimizing low-value care

 - Kenny Lin, MD, MPH

Hospitals and health systems have often needed to restrict nonemergent care during COVID-19 surges, with mixed effects on patients. Some patients may experience worse outcomes when necessary treatment or surgery is postponed, while others may avoid receiving unnecessary and potentially harmful (low-value) care. Of course, relying on a pandemic to reduce low-value care is not a strategy; at best, it's a blunt instrument that will be discarded when the public health emergency ends. Recent studies of pre-pandemic low-value care have further demonstrated the need for sustainable interventions.

Dr. Ishani Ganguli and colleagues described the use of 41 low-value medical services in a retrospective cohort of more than 11 million Medicare beneficiaries across 556 health systems. They found that the most common services were preoperative laboratory testing, prostate-specific antigen testing in men older than 70 years, and antipsychotic medications in patients with dementia. Characteristics of health systems associated with greater low-value care (based on a composite measure of the 28 most common services) were having a smaller proportion of primary care physicians, a larger proportion of patients of color, no teaching hospital, higher health care spending, and headquarters in the Southern or Western U.S.

Another recent study of Medicare claims data examined the prevalence and costs of hospital-acquired conditions and patient safety indicator events associated with a selection of low-value inpatient procedures. The investigators identified 231 hospital-acquired conditions and 1,764 patient safety indicator events associated with these procedures from 2016 to 2018, resulting in $3.16 million and $26.7 million in additional health care costs, respectively. For example, hospital-acquired conditions occurring during an admission for percutaneous coronary intervention extended length of stay by an average of 17.5 days and increased the cost of hospitalization by $22,000.

The Cochrane Library has created a special collection of systematic reviews on resource-intensive interventions "for which there is high or moderate certainty evidence that they confer clinically small or no effects, and for which there is some evidence of harm to patients." Examples include preoperative testing for cataract surgery, percutaneous vertebroplasty for vertebral compression fractures, and intensive follow-up strategies after treatment of non-metastatic colorectal cancer.

As Dr. Jennifer Middleton pointed out in a previous AFP editorial, changing physician behavior to minimize low-value care requires creating new workflows and systems of care. A systematic review of 131 articles on Choosing Wisely interventions in the U.S. through June 2019 found that the most effective interventions target clinicians rather than patients, are active rather than passive, and include multiple components. The type of low-value service targeted did not affect outcomes. Components of effective clinician-focused interventions included behavioral nudges, feedback / report cards, clinical decision support, electronic health record enhancements, clinician champions, education and academic detailing, and creating new clinical pathways.

The malaria vaccine's lessons for COVID-19

 - Jennifer Middleton, MD, MPH

Last week, the World Health Organization (WHO) endorsed the use of RTS,S (Mosquirix), a vaccine against malaria which targets Plasmodium falciparum in its sporozite phase. Mosquirix, given in 4 doses between ages 5 months and 3 years, is the first vaccine ever developed against a parasite. Plasmodium falciparum's range is limited to Africa, and the distribution of RTS,S will be appropriately prioritized to areas of greatest need there. 

RTS,S decreases the risk of severe malaria by 50% in the first year, though its effectiveness wanes to near zero after 3-4 years. Combining RTS,S with seasonal chemoprophylaxis further improves outcomes:

There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20.

Worldwide, malaria afflicts over 220 million people a year; in Africa, it kills an estimated 400,000 persons a year. Children bear its brunt, with 67% of malaria deaths occurring in children under the age of 5 years, and it causes profound morbidity in those who survive (and are often repeatedly reinfected). RTS,S will not singlehandedly eliminate malaria, but, in combination with bed nets and chemoprophylaxis, it could help prevent over 5 million cases of malaria - and over 23,000 child deaths - a year. 

RTS,S and the COVID-19 vaccine share some interesting parallels. The COVID-19 vaccines are also not 100% effective at preventing COVID-19 disease, but they have still saved hundreds of thousands of lives since their introduction as well as reducing the morbidities associated with COVID-19 infection. In combination with face masks and social distancing, the COVID-19 vaccines can provide a path out of the pandemic. Prioritizing COVID-19 vaccine supply to regions of the world still waiting for their first doses (instead of focusing on boosters for those already vaccinated) could maximize their life-saving capacity and reduce the risk of further viral mutation. Viewing these infectious diseases as complex, global challenges that require a multifactorial approach could lead to more effective collaboration, cohesive solutions, and more lives saved. 

In the meantime, we need to keep recommending COVID-19 vaccination as well as discuss preventive measures with patients planning travel to malaria-endemic regions. This AFP article on "Prevention of Malaria in Travelers" provides an overview of medications, insect repellents, and bed nets, and the Centers for Disease Control and Prevention (CDC) has additional information on malaria diagnosis and treatment. The AFP By Topic on Travel Medicine also includes this article on pretravel consultation along with a wealth of patient education handouts.

What we now know about multisystem inflammatory syndrome in children

 - Kenny Lin, MD, MPH

In May 2020, a previous AFP Community Blog post described an emerging COVID-19 associated, Kawasaki disease-like syndrome that became known as multisystem inflammatory syndrome in children (MIS-C). (The Centers for Disease Control and Prevention later identified a similar inflammatory syndrome in adults, MIS-A.) Over the past year, as family physicians, pediatricians, and children's hospitals have gained experience with treating patients with MIS-C, we now know more about differentiating it from Kawasaki disease and managing its major complications. A review article by Drs. John Darby and Jennifer Jackson in the September issue of AFP provided an overview and comparison of Kawasaki disease and MIS-C. Although Kawasaki disease primarily occurs in toddlers, MIS-C has been observed in patients from one week to 20 years of age, with a median age of 7 to 9 years. In the U.S., Hispanic and non-Hispanic Black children have been disproportionately affected by MIS-C, comprising 62% of all cases. Vomiting, diarrhea, and abdominal pain occur in 80% of patients, while neurocognitive symptoms affect about 20%. Additional symptoms of MIS-C can include hypotension secondary to cardiac dysfunction and systemic vasodilation.

Two observational studies of patients with MIS-C published in June 2021 added to the knowledge base but did not definitively identify the most appropriate treatment. A propensity-score matched analysis of 518 patients admitted to U.S. hospitals for MIS-C between March 15 and October 31, 2020 found that initial treatment with intravenous immune globulin (IVIG) plus glucocorticoids, compared to IVIG alone, was associated with a reduced risk of new or persistent cardiovascular dysfunction (a composite outcome of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2 of admission. In contrast, an international cohort study of 614 children with suspected MIS-C from 32 countries treated from June 2020 through February 2021 found no differences in a composite outcome of inotropic support or mechanical ventilation by day 2 or later between children who received IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.

A longitudinal cohort study of 50 patients admitted to a single U.S. medical center between April and June 2020 reported outcomes of MIS-C at 6 months. 31 patients required intensive care, and 33 developed left ventricular dysfunction, coronary dilation, or aneurysms. The mean length of stay was 5 days. After two weeks, only 9 patients had persistent ventricular dysfunction or other coronary abnormalities, though nearly half reported fatigue with ordinary activities. All 25 patients who presented for a 6-month follow-up visit were asymptomatic, with a single patient having left ventricular diastolic dysfunction. Although the rapid resolution of symptoms and cardiac abnormalities seen in this study is good news, it is unclear if these outcomes will persist given the much greater number of children with COVID-19 infections who were hospitalized during the summer of 2021. The best approach to preventing MIS-C remains reducing the risk of SARS-CoV-2 infection through vaccinating adolescents and - pending regulatory approval in the next few weeks - younger children.