Digest #52: A Spring Special

April 20, 2024 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we cover Perils of Accelerated Drug Approvals, Beta Blockers after MI, Naltrexone in Cirrhosis, COVID treatment for the low risk, and Aspirin in MASLD.  Effortlessly absorb important medical news, with our twice monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 52

04/19/2024

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
-Beth Garbitelli MD, Laura Glick MD, Alyssa Mancini MD

• Low risk, low benefit to Paxlovid? The NEJM recently published the results of EPIC-SR, the Phase 2/3, double-blinded, placebo-controlled trial demonstrating that nirmatrelvir/ritonavir (Paxlovid) did not shorten symptom duration in the standard risk setting.  1296 adults with symptomatic COVID-19 (PCR confirmed) who were at standard risk for severe COVID-19 or were fully vaccinated with at least one risk factor for severe disease were randomly assigned within 5 days of symptom onset to receive 5 days of nirmatrelvir/ritonavir or placebo.  The median age of study participants was 42 and a majority had received previous vaccination, with common risk factors for severe disease including increased BMI, smoking, and hypertension.  There was no significant difference between the treatment and placebo groups in median time of sustained alleviation of COVID-19 symptoms (12 days vs. 13 days, P=.060),  viral rebound, or COVID-19 related hospitalization or death. (LG) 
• Asymptomatic Bacteriuria and Risk of Bacteremia. A retrospective study just published in JAMA looked at rates of bacteremia in patients with asymptomatic bacteriuria (ASB). This multi-hospital cohort study included over 11,500 hospitalized patients with ASB from 68 hospitals across the United States (median age 78.2; 74.2% female). In this cohort, 1.4% of patients developed bacteremia from a presumed urinary source. Notably, in patients with altered mental status but no other systemic signs of infection, only 0.7% developed bacteremia from a presumed urinary source, supporting 2019 IDSA guideline recommendations to look for other causes and observe (instead of empirically treating with antibiotics) in older patients with ASB and non-localizing cognitive symptoms but no systemic symptoms. (LG) 
• Naltrexone Safety in Cirrhosis. Treating alcohol use disorder (AUD) in alcohol-related cirrhosis presents a  clinical challenge, given concerns about the safety of various pharmacologic interventions in cirrhosis. A new retrospective cohort study out of the Veterans Affairs system evaluated liver injury outcomes after naltrexone initiation in 3285 patients with cirrhosis. Drug-induced liver injury (DILI) was assessed based on alanine transaminases and alkaline phosphatase elevations and The Roussel Uclaf Causality Assessment Method (RUCAM), based on data captured within 3 months of naltrexone initiation.  Only 2% of patients with cirrhosis on naltrexone demonstrated liver enzyme elevations, with none thought to be related to DILI based on RUCAM and patterns of liver injury.  No deaths or decompensations were attributed to naltrexone. (BG) 
• Daily low-dose aspirin reduces hepatic fat content in MASLD. JAMA recently published the results of a phase 2, randomized, double-blind, placebo-controlled trial of 80 adults (mean age 48 years, 55% women) with metabolic dysfunction-associated steatotic liver disease (MASLD) without cirrhosis who were randomized 1:1 to receive aspirin 81 mg or placebo once daily for 6 months. The mean absolute change in hepatic fat content via magnetic resonance spectroscopy (MRS) at 6-month follow up was -6.6% with aspirin vs. +3.6% with placebo (mean difference -10.2%; 95% CI -27.7% to -2.6%). Treatment with aspirin also significantly increased the proportion of patients with 30% or greater relative reduction in hepatic fat. Similar adverse events (URI, arthralgias) were reported with aspirin and placebo. (AM) 
• In lower-risk patients after acute MI, beta blockers may not benefit. The NEJM recently published results from REDUCE-AMI, an open-label trial conducted at 45 centers in Sweden, Estonia, and New Zealand.  5020 patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (> 50%) were randomly assigned to long-term treatment with a beta-blocker (metoprolol or bisoprolol) or no beta-blocker.  After 3.5 years of median follow-up, the composite of death from any cause or new myocardial infarction occurred in 7.9% of those in the beta-blocker group and 8.3% in the no-beta-blocker group (HR 0.96; 95% CI 0.79-1.16), with no significant between-group differences in secondary endpoints including all-cause or cardiovascular death, myocardial infarction,  or hospitalization for heart failure or atrial fibrillation.  Safety events were similar in both groups. It is worth noting that a lower-than-anticipated event rate in the trial led to limited power to detect between-group differences. (AM) 

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

“Speaking of Stigma” – Medical student Sudharshini Prasanna at University of Houston reflects on her experience with tuberculosis treatment and the prevalence of stigma in medicine. 

Bake with us! Beth is trying her hand at carrot cake cinnamon rolls this week. Check out a few recipes here and here. 

– Beth “Garbs” Garbitelli MD 

The Main Course

Alexander Chaitoff MD MPH 

Cancer Drug Approval – Is there such a thing as too fast? 
Cancer, the second leading cause of death in the United States, occupies a special place in healthcare. Everyone seems to know someone who has had it –and being thought of as the Emperor of All Maladies means a lot of money is spent on studying it. In fact, in some instances more money is spent on research for certain kinds of cancer than would be expected when accounting for the actual burden of disease in the population.

Partly because cancer holds a special place in the public consciousness—and partly because cancer therapies are reimbursed well—there is immense pressure and immense incentive to make new treatments available to patients quickly.

Accelerated Approval 
One mechanism by which treatments are made rapidly available is via accelerated approval. This is a pathway through which drugs treating serious conditions for which there is  unmet need can be approved by the Food and Drug Administration (FDA), based on changes in a surrogate endpoint.  Initially used for HIV medications to rapidly provide access to drugs for a disease without any approved treatment options, the accelerated pathway has become a common pathway in oncology, such that approximately one-third of new cancer drugs utilize the pathway for initial approval.  This pathway, and the use of surrogate endpoints in clinical trials, has allowed for initial studies of efficacy to be completed using shorter follow-up and smaller sample sizes. 

And while it sounds great to make new drugs available faster, surrogate measures don’t always correlate well with important outcomes.  To illustrate this point, consider one of the most common surrogate outcome measures used – progression free survival.  Progression-free survival (PFS) generally refers to objective progression of cancer on radiologic scans (or clinical progression).   And while PFS is one of the most commonly used surrogates in oncology, its correlation with patient-important outcomes, such as overall survival, may be variable–both from disease to disease, and in the new era of therapies using novel biologic mechanisms and leading to  improvements in post-progression survival.   Of course, survival isn’t the only thing that matters, but there is also limited data suggesting progression free survival equates to improved quality of life—with one study of 147 trials suggesting only a weak correlation (r=0.34) between progression free survival and quality of life.  

Given that many cancer drugs go through the accelerated approval process, they are evaluated and approved – and ultimately given to patients –based on these surrogate endpoints, which may or may not be strongly correlated with outcomes we really care about.  Fortunately, the FDA requires confirmatory trials, and accelerated approvals can be revised or withdrawn based on confirmatory trial data.   But this begs the question—how many of these drugs actually help patients?

Not enough confirmatory evidence all cancer drugs work
According to a new study in JAMA, many cancer drugs granted accelerated approval do not end up demonstrating clinical benefit in extending patients’ lives or improving quality of life. In this study, researchers identified 129 cancer drug-indication pairs that received accelerated approval between 2013 and 2023 and examined what happened in confirmatory trials.  Of the 46 drugs with >5 years of follow-up, only 43% of the indications demonstrated clinical benefit in confirmatory testing.  This finding adds to a 2019 paper suggesting that only 20% of cancer drug indications receiving accelerated approval from the FDA showed improvements in overall patient survival in subsequent confirmatory trials.

Where to go from here?
These challenges around accelerated approval are not unique to cancer drugs.  For example, a novel ALS medication approved under the accelerated pathway was recently pulled from the market after null confirmatory testing. However, as soon as a cancer drug is granted accelerated approval, it is often included in clinical guidelines.  Moreover, because cancer is highly prevalent, because drugs granted accelerated approval become available, and because the drugs are both toxic and expensive, cancer drug approvals warrant particular thought.

It’s unlikely there is a simple fix to this issue. Rather, a multifaceted approach–including identifying better surrogate measures as diseases and therapies change and policy fixes that require pharmaceutical companies to rely more on clinical and patient-important endpoints for ultimate approvals–is likely needed. A thoughtful approach may ultimately keep new drugs coming, while not exposing patients to side effects without evidence of clinical benefit. 

Read The JAMA Study HERE!

Digestifs

Before you go….
we’ve got a few nibbles!

Consolidate your learning with a Quiz!  

This week on The Curbsiders:  In Episode #435, dive deep into neck pain with Dr. Anthony Mikula (@anthony_mikula), from the mechanical to the neuropathic.  Learn the questions to ask on history, how to perform a good physical exam, and when to obtain imaging. This one will make neck pain a breeze. 

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Until next time, keep that brain hole digesting! 

The Curbsiders Digest

Issue 52

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Disclosures:
Beth Garbitelli,  Alyssa Mancini, Laura Glick, and Nora Taranto report no disclosures.

Alex Chaitoff reports consultancy for Alosa Health 

Kate Grant reports no disclosures 

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