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Look at us.
Who would have thought we’d be at the end of 2025, actually engaging with medical literature? It wasn’t on my bingo list at all.
Cheers to us 🍻
Before we close out for the year, we have one more Friday Handover.
Do me this favour and cherish it. As it certainly cherishes you.
👋 Happy Friday. Here’s what we got:
🦸 The Fantastic Four: How Heart Failure became a 4-drug Job
🧛 What Happens When You Put 40,000 Haematologists in a Room?
🧠 QuickBits: Other Top Stories of The Week
If you want to read any previous editions of The Handover, you can on our website.
GUIDELINE CHANGE: JOURNAL CLUB
🦸 The Fantastic Four: How Heart Failure became a 4-drug Job
We all know the Heart Failure Formula™:
Start with this drug, add a sprinkle of that one … any luck? No? Just slap on another!
Just like hypertension, a slow stepwise approach (🥱) is King in HFrEF.
But wait, why is that? Why not just whack it with everything we’ve got?
Well, that’s the latest guideline change!💥
In an Avengers-style move, cardiology has deployed the entire heart failure squad up front:
ACE-inhibitors + Beta-blockers + Spironolactone
And who else?
The most exciting addition is medicine’s new wonder boy, the ✨SGLT-2 inhibitor✨.
Ignoring that pesky little side effect of your naughty bits necrosing, they’re pretty incredible at well … most things. And HFrEF is no exception.
The DAPA-HF and EMPEROR-reduced studies, both published in NEJM, examined the effect of dapagliflozin and empagliflozin, respectively, on 8474 participants (with AND without T2DM).
Here’s the rundown:
In DAPA-HF, the proportion of patients with worsening HF (hospitalisation / urgent IV therapy) or CV death was 16.3% vs 21.2%, dapagliflozin vs placebo. Dayum. (HR 0.74 (95% CI 0.65-0.85) p<0.001)
Plus team dapagliflozin had fewer serious adverse renal events!
Similarly, only 19.4% of those on empagliflozin in EMPEROR suffered CV death or hospitalisation for HF vs 24.7% on placebo (HR 0.75 (95% CI 0.65-0.86) p<0.001)
Not just that, the effect was consistent regardless of diabetes. AND, it was in addition to standard HFrEF therapy.
Which is the key point🔑:
SLGT-2 inhibitors didn’t swoop in as a solo hero. They worked because they joined the team.
ACEis (/ARNIs) were already inhibiting RAAS-mediated vasoconstriction, beta blockers were calming the chronic sympathetic panic and mineralocorticoid receptor antagonists (ie. spiro) were busy blocking the effects of aldosterone.
Chuck in some SGLT2 osmotic diuresis + ⬇️preload, and the squad is looking pretty stacked:
And when the evidence was this clear, NICE took notice. In their 2025 review of heart failure medications, they evaluated all of the above to figure out what worked and was cost-effective.
And the conclusion? Just like the NEJM trials. Patients do better when they’re on the Fantastic Four early. Not sequentially. But as standard first-line therapy, assuming they can tolerate it.
Economically, NICE also looked at models where the four were introduced earlier rather than later. These analyses showed that early combination therapy wasn’t just clinically better, but cost-effective for the NHS.
In other words, getting patients on all four foundational drugs sooner shrinks hospital admissions, improves quality of life and doesn’t break the bank
Once upon a time, adding a third or fourth drug felt… ambitious.
Now, it's the first line.
The science is solid, the economics check out, and the results speak for themselves.
So the new HFrEF formula is clear:
Assemble early
Protect the pump
Profit💅
RESEARCH UPDATE
🧛 The Result of 40,000 Haematologists in 1 Room?
Haematologists.
The most reclusive medical speciality.
Away from the rest of hospital medicine.
Inspecting blood films till their hearts' content.
Once a year, these blood lovers gather to discuss all things bloody at the ASH conference.
Thats right…
Leukaemias, anaemias and the vampire movie of the year(it was unanimously Sinners this time round).
This year, the study that got all the haematologists' gonads going was the MajestTEC-3 trial, published in NEJM
So let me ask you this:
When you think of multiple myeloma(MM), what comes to mind?
Too many plasma cells…
The CRABBI mnemonic…
Maybe rouleaux formation or raindrop skull if you're extra keen(which I know you all are 😑)...
Management is chemo right? Yes, you’re right!
But MM is a crafty little blood cancer. It just can’t stay down. Relapsing MM is a big concern. And so, when the excess plasma cells return in full force, we give it our full artillery force.
Daratumumab - a CD38 antibody that depletes malignant plasma cells, + Dexamethasone - a steroid, + either Pomalidomide, an immunomodulatory drug or Bortezomib - a proteasome inhibitor.
But even after that, the Myeloma won’t just stay down. The treatment pathway after is a bit convoluted. But the consensus is that if triple therapy doesn’t work, you’re pretty much cooked.
Until now…
This head-to-head trial pits triple therapy against something new – duel therapy. A dual therapy of daratumumab and teclistamab
Teclistamab(tech-li-star-mab) is a fancy antibody that binds to CD3 on T-cells and BCMA on the myeloma cells. Essentially, handholding the condemned cell to its executioner. Thus enhancing cell killing activity.
This study took 587 patients with MM who’d received one to three previous lines of therapy. They were then randomly assigned either:
Standard Care Group(triple therapy) group - 296 patients or
Teclistamab- Daratumumab group - 291 patients.
They continued treatment until progression, unacceptable toxicity, death or withdrawal. The primary endpoint was progression-free survival.
So what did they find?
At a median follow-up of 34.5 months, Teclistamab-Daratumumab absolutely obliterated triple therapy
36 month Progression-Free Survival: 83.4% vs 29.7%
Complete Response: 81.8% vs 32.1%
Overall Response Rate: 89% vs 75.3%
I mean, just look at this graph. A thing of true academic beauty.
Now, Teclistamab isn’t a newcomer. It’s been approved by NICE and the FDA… as a 4th line medication(wasn’t rated whatsoever). This staggering finding is sure to have it leapfrog to number 1.
But, maybe not so fast. The side effect profile here is pretty insane:
Serious Adverse Events: Occurred in 70.7% of the teclistamab group vs. 62.4% in the standard group
Infections: Any-grade infections were reported in 96.5% of the teclistamab group. Fatal infections were higher in this group (4.6% vs. 1.4%). 96.5% is crazy icl.
Cytokine Release Syndrome (CRS): This occurred in 60.1% of patients receiving teclistamab, but all cases were low-grade (Grade 1 or 2) and resolved without treatment discontinuation.
So you gotta balance the good with the bad, like all of medicine.
But to the haematologist. I see the vision.
The teclistamab hype is real.
QUICKBIT: OTHER NEWS YOU SHOULD KNOW
Is a new big daddy of GLP-1 RAs in town? It looks like it 👀
As in the battle for the most effective weight-loss drug, Eli Lilly is pulling away.
Clinical trials have proven Tirzepatide to be the most effective drug for weight loss so far. But Eli Lilly seeks to extend its lead by pushing the final boss of weight loss, Retaturtude, through the research phase. It’s a triple agonist(how greedy), which has now made it through phase 3 clinical trials
Results of the TRIUPH-4 trial showed that, on the highest dose, weightloss was 26.6% after 68 weeks. Better yet, it had a 27.5% improvement in knee osteoarthritis compared to placebo. Not too shabby at all. Side-effects were a bit shakier tho.
Whilst the Welsh don’t win much, they have seemingly won their battle against the government over pay. A “historic new contract” has been agreed between the Welsh BMA and NHS Wales Employer for a “4% additional investment”. This reduced the real-terms cut from 19.1% to 16.1%, with an overwhelming majority (83%) agreeing to the contract.
The other perks seem a little intangible: “measures to tackle medical employment” and “reforms to study budgets”, but at least they're happy.
For my medtech readers, AI proves itself to be overpowered once again. A new AI model was tested in a trial published in Nature Medicine. The aim was to see if the AI model could predict and detect liver cirrhosis risk from a patient's ECG reading.
A total of 15,000 adults were included and tested during routine medical checkups. The tool doubled detection (1.0% vs 0.5%) and found “high risk” cases for advanced disease in 4.4% of cases vs the controls 1.1%.
This study tested whether identifying women at high risk of pre-eclampsia at 36 weeks and planning an early-term delivery could reduce pre-eclampsia.
Women who were screened and delivered early if high risk had fewer cases of pre-eclampsia than those receiving usual care. Importantly, this approach did not increase caesarean sections or neonatal complications. In short, planned early delivery for high-risk women near term safely reduces pre-eclampsia.
Read the full paper using the link above
BMA:
As the bickering battle between Wes and the BMA continues, Senior NHS bosses are calling for a change in how this war is conducted.
An independent arbitrator (i.e. a handsomely paid referee) is being suggested to mediate the conversations between the parties.
“This would facilitate a more constructive dialogue between the government and the BMA’s resident doctors committee and help to bring this dispute to an end, once and for all.”
Now, where can we find a medically-literate, wise, independent party that’s well-versed in managing broken-down relationships 🤔…
Dr Phil – The NHS is calling!
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