Thursday, April 3, 2025

UDLCO CRH : Wildebeest model of EBM values from a journal club around a recent but small 'big-pharma' question around aspirin vs clopidogrel mono therapy following post PCI dual antiplatelet therapy

Summary: 


The conversation revolves around a journal club discussion on a study comparing the efficacy of clopidogrel versus aspirin monotherapy in high-risk patients post-PCI (percutaneous coronary intervention). The discussion focuses on the absolute risk reduction (ARR) and number needed to treat (NNT) to better understand the magnitude of the benefit and draws an analogy with a wildebeest crossing a river, who needs to choose which part of the river bank will be safer in terms of either getting swept away in the current and drowning or getting eaten by a crocodile! In this particular study it turns out If I were a patient who underwent a PCI along with 5506 patients (or a wildebeest crossing a crocodile filled river with 5506 other wildebeests ) and was randomly assigned to chewing clopidogrel along with 2752 patients (2752 wildebeests crossing from the clopidogrel bank) compared to 2754 patients who continued to gulp aspirin (2754 wildebeests crossing from the aspirin bank), would I be elated by the fact that after 2·3 years, 2752-92=2660 patients (wildebeests) like me survived in my clopidogrel group (92 wildebeests got eaten by crocodiles) and 2754-128= 2626 people like me survived in the aspirin group (128 wildebeests got eaten)?

*Key Words:*

- Aspirin
- Clopidogrel
- PCI (Percutaneous Coronary Intervention)
- Absolute Risk Reduction (ARR)
- Number Needed to Treat (NNT)
- Evidence-Based Medicine (EBM)
Wildebeest model of EBM values 






Conversational learning Transcripts with humans in the loop where the journal article was floated:

[02/04, 07:07]human user 1: ASPIRIN days are numbered by " SMART CHOICE 3 " Data on post POST PCI.

[02/04, 08:01]human user 2 : Time to say 👋 bye  bye to Aspirin

[02/04, 08:13]cm: Please share a link to the original full text if possible


[02/04, 08:35]human user 2: Smart choice 3





[02/04, 08:37]human user 3 : Editorial comments


[02/04, 10:16]cm: The EBM absolutist narrative interpretation:

If I were a patient who underwent a PCI along with 5506 patients (or a wildebeest crossing a crocodile filled river with 5506 other wildebeests ) and was randomly assigned to chewing clopidogrel along with 2752 patients (2752 wildebeests crossing from the clopidogrel bank) compared to 2754 patients who continued to gulp aspirin (2754 wildebeests crossing from the aspirin bank), would I be elated by the fact that after 2·3 years, 2752-92=2660 patients (wildebeests) like me survived in my clopidogrel group (92 wildebeests got eaten by crocodiles) and 2754-128= 2626 people like me survived in the aspirin group (128 wildebeests got eaten)?

The EBM relativist statistical interpretation:

The key finding is that clopidogrel reduced the primary endpoint (all-cause death, myocardial infarction, or stroke) with a hazard ratio of 0.71 (95% CI 0.54–0.93; p=0.013).

The study evaluates the efficacy of clopidogrel versus aspirin monotherapy in high-risk patients post-PCI.  The absolute difference in events was 36, mainly driven by deaths (20) and myocardial infarctions (19). However, concerns include an unexpectedly low number of observed events (210 vs. expected 402), lack of multiple testing adjustments, and a low fragility index (FI of 7 for the primary endpoint, 3 for MI), indicating statistical instability.

From an absolute risk perspective, the study shows a 2.2% absolute risk reduction (ARR) in primary events (6.6% with aspirin vs. 4.4% with clopidogrel over three years). While relative risk (RR) shows a 29% reduction, ARR highlights the practical impact—only 2 fewer events per 100 patients treated.

Should a Patient Be Elated?

Statistically? Yes, because clopidogrel led to fewer adverse events.

Clinically? Maybe. A 1.31% absolute reduction is modest but meaningful.

Individually? If you’re risk-averse, you might prefer clopidogrel. If you weigh cost, side effects, or other factors, you might still consider aspirin.

The above diatribe didn't have much effect in the group as the subsequent conversations reveal below:

[02/04, 11:13]hu3: It is intuitive to think 
If clopidogrel is used after genotyping ,there is further increase in outcomes or it will be counterbalanced by bleeding 
Inputs pl


[02/04, 11:38]hu2: I can't find a single reason to prefer Aspirin monotherapy over clopidogrel monotherapy in CCS patients . 
But I have quite a number of reasons and evidence which prove the superiority of clopidogrel over Aspirin monotherapy.

[02/04, 11:42]hu4: More bleeding, surgeons not confident to operate on Clopidogrel, no evidence base of superiority, resistance high in Asians 
Only no sponsors for cheap aspirin

[02/04, 12:07] hu5 : Second that

[02/04, 12:20]hu2: All RCTs and meta analysis have shown including the HOST EXAM study that bleeding was 25 % more with Aspirin than clopidogrel


[02/04, 12:21]hu2: All RCTs and meta analysis have shown including the HOST EXAM study , Panther study, etc  that efficacy in reducing MACE was 25 % more with  clopidogrel than Aspirin

[02/04, 12:21] hu2: Including this recent SMART CHOICE 3

[02/04, 12:22]hu2: Tell me a single RCT which shows superiority of Aspirin over Clopidogrel


[02/04, 12:23]hu2: As far as clopidogrel resistance is concerned it was theoretical and never proven of any clinical relevance in any of the trials

[02/04, 12:27]hu3: My question is not related to aspirin
It is genotype based higher efficacy vs bleeding.
It is different


[02/04, 12:33]hu2: In TROPICAL ACS study , guided de escalation was done with clopidogrel after doing platelet function test . But guided strategy was not found to be superior over un guided strategy for clopidogrel


[02/04, 12:46] hu3: This is difficult, the issue of  genotypic based efficacy questionable !


[02/04, 12:47]hu6: What are the bleeding rates in 2 cohorts


[02/04, 12:51]hu7: It was a non inferiority design trial sir


[02/04, 12:52] hu8: Decide are we talking about CCS or ACS
IF ACS I am for clopidrogrel
If CCS - nothing to choose 
But Ecosprin is non inferior with less bleeding 
If GI bleed aspirin is preferred over clopidogrel


[02/04, 12:58]hu2: All  trials and meta analysis have suggest that bleeding is more with Aspirin than clopidogrel.
If you have any trial saying opposite  this , pls tell us .


[02/04, 12:58]hu2: I am talking about CCS only


[02/04, 13:01]hu2: The SMART CHOICE , HOST EXAM , PANTher , CAPRIE, etc all were done in CCS only and has shown superiority of clopidogrel over aspirin


[02/04, 13:14]hu9: More GI bleed with Aspirin imo. 
Even GE agree.


[02/04, 13:36] hu10: I agree ,aspirin bleeds more


[02/04, 13:38]hu3: I think it am not able to place my question. 
Non inferiority can not make you choose clopidogrel. 
My question is genotype based data of superiority of clopidogrel vs bleeding in same group.


[02/04, 13:38]hu8: Today aspirin and clopidogrel both have class 1 A recommendation


[02/04, 15:04] hu11 : Aspirin is cheaper. 
Aspirin has shown to reduce colorectal cancers when taken for more than 5 years. 
Advantage of clopidogrel over aspirin- no side effect of hyperuricemia🙏🙏


[02/04, 15:08] hu12: Neutral effect data


[02/04, 15:09] hu13: Many gastros after GI bleed if single antiplatelet is needed prefer aspirin over clopidogrel

[02/04, 15:09]hu13: along with PPI

[02/04, 15:10]hu13: As clopidrogrel hampers healing of mucosa
Aspirin with prostaglandin analogous are the choice by GI

[02/04, 15:16]hu13: Aspirin vs Clopidogrel: Antiplatelet Agent of Choice for Those With Recent Bleeding or at Risk for Gastrointestinal Bleed - PMC


[02/04, 15:17] hu2: HOST EXAM ( RCT ) .. both efficacy as well as safety was 32% in favour of Clopidogrel

[02/04, 15:18]hu2: Panther : More bleeding and more MI with Aspirin as compared to clopidogrel


[02/04, 15:19]hu2: CAPRIE : old RCT showed net clinical benefit in favour of clopidogrel


[02/04, 15:19]hu2: One more meta analysis in favour of clopidogrel


[02/04, 15:20]hu2: One more meta analysis showing less MI with clopidogrel


[02/04, 15:21]hu2: The reason is the main pathway of platelet inhibition is P2Y12 and not cyclooxegenase .That's why less MI with clopidogrel than aspirin


[02/04, 15:21]hu13: Those who have passed STRESS TESTING OF DAPT for 6-12 months 
Trial result will be different.
Real world data will be different.
Get one abdominal surgery on deplatt see results
GI surgeries on aspirin is often done in CAD Patients with out BARC 3-5 bleeding


[02/04, 15:22]hu13: Driver was only PAD
neither stroke nor MI

[02/04, 15:23]hu13: NS for MI/Stroke

[02/04, 15:24]hu14: Last three markers are trends ,not significant


[02/04, 15:25] hu3: This discussion pertains to after dapt ,whatever your time frame .
This is not sapt head on data in acute event

[02/04, 15:25] hu2: Tell me one trial which says that Aspirin is more efficacious than Clopidogrel

[02/04, 15:26]hu13: None 
It can not be

[02/04, 15:26]hu13: As more efficacy 
More bleeding

[02/04, 15:27]hu2: Now tell me one RCT which says that more bleeding with clopidogrel than ASpirin

[02/04, 15:27]hu13: GI 
CEREBRAL CIRCUIT
I AM NOT EXPERT
ABC2D SCORE FOR GI


[02/04, 15:29] hu13: CAPRIE IS SAPT ,WHICH IS NO LONGER PRACTISED.
TODAY DAPT IS THE RULE IN ACUTE EVENTS

[02/04, 15:59]hu13: 8.6 % VS 0.7% in bleeding
: Jan 2025
This is GI Circuit

[02/04, 16:03]hu14: Asprin + Esmoprezole vs Clopidogrel? How is that fair comparison?

[02/04, 16:04]hu13: Clopidrogrel and esomeprazole in both arm

[02/04, 16:05]hu2: This trial is comparing a combination of Aspirin + PPI vs Clopidogrel alone .
So this is not a fair comparison. 
The PPI should be in both arms because we know that PPi does reduce GI bleed


[02/04, 16:05]hu14: No. Please read the study carefully

[02/04, 16:05]hu2: Exactly
[02/04, 16:05]: No

[02/04, 16:08]hu14: I use Aspirin only for 3-12 months in all my cases. Rest Clopidogrel. This has been my protocol for last 3-4 years
 12 m only in ACS
: Aspirin causes GI bleeding much more than clopidogrel
One year after plasty even in patients with so called resistance to clopidogrel it shouldn’t matter 
Clopidogrel would probably be safer than aspirin as the data suggests. However surgeons won’t operate on clopidogrel in an emergency. Probably can have a balanced approach and individualise therapy ? Using wither should be ok. 
If we follow our patients up with serial Hb some of them have a gradual drop and changing to clopidogrel probably is better because most of this is GI bleeds. 
My two bits.

[02/04, 16:15]hu14⁩ : With platelets available, surgeons will operate in emergency
: Now a days surgeons are far more compliant

[02/04, 16:20]hu15: No . You don’t know the struggle

[02/04, 16:23]hu16: What about Prasugrel as  long term SAPT post ACS?

[02/04, 16:23]hu14: I think too strong

[02/04, 16:24] hu13: Post 1 year Clopidogrel should be enough

[02/04, 16:25]hu3: Just a thought … will we ever have a study of SAPT vs no APT post 2 years ? Is it ethical or possible . One wonders. Believe not

[02/04, 16:28]hu13: In GI bleed situations clopidogrel plus PPI interaction are more complex than aspirin plus PPI and gastros seem to prefer aspirin with PPI

[02/04, 16:28]hu13: this study also suggests the same

Conversational Transcripts between two humans in the loop enthusiastically prompting and learning from many LLMs: 

[02/04, 09:37]cm: 👆 keeping in line with our previous fruitful journal club where we were able to demonstrate the superiority of absolute risk (an academic learning tool) over relative risk (a pharma earning tool) let's analyse the data in the above study


[02/04, 09:37]cm: I'm doing it manually meanwhile


[02/04, 09:37]asml llm: Surely


[02/04, 09:39]cm: Can also try med arena that will automatically take the same through a multiple LLM processing journey


[02/04, 09:43]asml llm: The study evaluates the efficacy of clopidogrel versus aspirin monotherapy in high-risk patients post-PCI. The key finding is that clopidogrel reduced the primary endpoint (all-cause death, myocardial infarction, or stroke) with a hazard ratio of 0.71 (95% CI 0.54–0.93; p=0.013). The absolute difference in events was 36, mainly driven by deaths (20) and myocardial infarctions (19). However, concerns include an unexpectedly low number of observed events (210 vs. expected 402), lack of multiple testing adjustments, and a low fragility index (FI of 7 for the primary endpoint, 3 for MI), indicating statistical instability.

From an absolute risk perspective, the study shows a 2.2% absolute risk reduction (ARR) in primary events (6.6% with aspirin vs. 4.4% with clopidogrel over three years). While relative risk (RR) shows a 29% reduction, ARR highlights the practical impact—only 2 fewer events per 100 patients treated.

What specific aspects would you like to analyze further?

[02/04, 09:57]cm: Very useful 👏👏

Encouraged by the previous journal club, I'm working on a new patient centered way to share the results in an absolutist EBM manner!

For example @⁨Meta AI⁩ in this study result pasted below can you answer the question below:

If I were a patient who underwent a PCI along with 5506 patients and was randomly assigned to chewing clopidogrel along with 2752 patients and compared to 2754 patients who continued to gulp aspirin, would I be elated by the fact that after 2·3 years lesser people died or had an MI or stroke (the primary endpoint) as in 2752-92=2660 patients in my clopidogrel group and more people died as in 2754-128= 2626 patients in the aspirin group?


[02/04, 09:57] Meta AI: Congratulations on working on a patient-centered approach to sharing study results!

Regarding the study you mentioned, I'll help you break down the results.

It appears you're describing a randomized controlled trial (RCT) comparing two groups:

1. *Chewing clopidogrel group* (2752 patients)
2. *Aspirin group* (2754 patients)

The primary endpoint was a composite of death, myocardial infarction (MI), or stroke.

After 2.3 years, the results were:

- *Chewing clopidogrel group*: 92 events (death, MI, or stroke) occurred, leaving 2660 patients event-free.
- *Aspirin group*: 128 events occurred, leaving 2626 patients event-free.

To answer your question: As a patient in the chewing clopidogrel group, you might be pleased to know that your group had:

- Fewer events (92 vs. 128)
- A slightly higher number of patients remaining event-free (2660 vs. 2626)

However, it's essential to consider the absolute risk reduction and the number needed to treat (NNT) to better understand the magnitude of the benefit.

Would you like me to help with calculating the absolute risk reduction and NNT?


[02/04, 09:58]cm: @⁨Meta AI⁩ yes please share the NNT in this study


[02/04, 09:58] Meta AI: To calculate the Number Needed to Treat (NNT), we need to determine the absolute risk reduction (ARR) between the two groups.

Based on the numbers you provided:

- *Chewing clopidogrel group*: 92 events (death, MI, or stroke) out of 2752 patients
- *Aspirin group*: 128 events out of 2754 patients

First, let's calculate the event rates:

- *Chewing clopidogrel group*: 92/2752 ≈ 0.033 (or 3.3%)
- *Aspirin group*: 128/2754 ≈ 0.046 (or 4.6%)

Now, let's calculate the absolute risk reduction (ARR):

ARR = Event rate in aspirin group - Event rate in clopidogrel group
= 0.046 - 0.033
= 0.013 (or 1.3%)

Finally, let's calculate the Number Needed to Treat (NNT):

NNT = 1 / ARR
= 1 / 0.013
≈ 77

So, the NNT is approximately 77. This means that 77 patients would need to be treated with chewing clopidogrel instead of aspirin to prevent one additional event (death, MI, or stroke) over 2.3 years.

Keep in mind that the NNT is just one aspect to consider when evaluating treatment options. Other factors, such as potential side effects, costs, and patient preferences, should also be taken into account.


[02/04, 10:01]asml llm: 

Based on the scenario provided, here's a patient-centered breakdown using an **absolutist EBM perspective**:

---

### **Key Results**
- **Clopidogrel group (you):**  
  92/2752 patients experienced death, MI, or stroke over 2.3 years (**3.3%** absolute risk).  
- **Aspirin group:**  
  128/2754 patients experienced death, MI, or stroke over 2.3 years (**4.6%** absolute risk).  

---

### **What This Means for You**


1. **Absolute Risk Reduction (ARR):**  
   You had a **1.3% lower risk** of death/MI/stroke compared to aspirin.  
   - *Example:* If 100 people like you took clopidogrel instead of aspirin, ~1–2 fewer would experience these events over 2.3 years.

2. **Relative Risk Reduction (RRR):**  
   Clopidogrel reduced your risk by **~28%** compared to aspirin.  

3. **Number Needed to Treat (NNT):**  
   ~77 patients like you would need to switch to clopidogrel (instead of aspirin) for 2.3 years to prevent 1 death/MI/stroke.  

---

### **Should You Be "Elated"?**


- **Statistically significant?**  
  Assuming this difference is statistically significant (e.g., p < 0.05), clopidogrel is superior for the primary endpoint.  


- **Clinically meaningful?**  
  A 1.3% ARR is modest but meaningful for a serious outcome like death/MI/stroke.  


- **Trade-offs:**  
  If clopidogrel had similar side effects/costs as aspirin, this benefit would likely be worthwhile. If it caused more bleeding (not specified here), that would need weighing.  

---

### **Bottom Line**  


Yes, you should feel reassured: clopidogrel **reduced your risk** of major adverse events compared to aspirin. While the absolute benefit is small (1.3%), it reflects a real advantage in a high-stakes outcome. However, "elation" depends on your values—some patients prioritize even modest risk reductions, while others focus on larger effects.  


[02/04, 10:03]cm: Excellent point about values!

If you recall Trisha's commentary article on values, this will be very useful for the commentary I'm currently working on!


[02/04, 10:06]asml llm:


Your absolutist EBM (Evidence-Based Medicine) framing is insightful! However, let's examine the numbers carefully.

Clopidogrel Group: 2752 patients → 92 had primary endpoint events → 2660 remained event-free

Aspirin Group: 2754 patients → 128 had primary endpoint events → 2626 remained event-free


At first glance, a patient might be elated that more people in the clopidogrel group remained event-free (2660 vs. 2626). 

However, an absolutist EBM perspective requires looking at the absolute risk difference:

Absolute risk of primary endpoint in Clopidogrel = 92 / 2752 ≈ 3.34%

Absolute risk of primary endpoint in Aspirin = 128 / 2754 ≈ 4.65%

Absolute risk reduction (ARR) = 4.65% - 3.34% = 1.31%

Number Needed to Treat (NNT) = 1 / 0.0131 ≈ 76


This means that for every 76 patients given clopidogrel instead of aspirin, one primary event (death, MI, or stroke) is prevented.

Should a Patient Be Elated?

Statistically? Yes, because clopidogrel led to fewer adverse events.

Clinically? Maybe. A 1.31% absolute reduction is modest but meaningful.

Individually? If you’re risk-averse, you might prefer clopidogrel. If you weigh cost, side effects, or other factors, you might still consider aspirin.

[02/04, 10:08) cm: All three outputs from same LLM? Which one?

[02/04, 10:11]asml : The first response was of DeepSeek, the second one was of Scholar ChatGPT and the third one of ChatGPT.

[02/04, 14:32]asml llm: Sure! Here's an academic and professional analysis of the article:

### **Key Research Context and Objectives**
This article presents findings from the SMART-CHOICE 3 trial, a multicenter, randomized, open-label study designed to evaluate the efficacy and safety of clopidogrel versus aspirin monotherapy for patients at high risk of recurrent ischemic events following percutaneous coronary intervention (PCI). The research builds on existing evidence about long-term antiplatelet therapy strategies and seeks to address uncertainties regarding the optimal single-antiplatelet regimen for secondary prevention.

### **Methodological Framework**
The study involved 5506 participants from South Korea who had completed a standard duration of dual antiplatelet therapy (DAPT) after PCI with drug-eluting stents. Participants were randomized to receive either clopidogrel (75 mg daily) or aspirin (100 mg daily), and outcomes were measured over a median follow-up period of 2.3 years. The primary endpoint was the cumulative incidence of major adverse cardiac and cerebrovascular events (MACCE), which included death, myocardial infarction, and stroke. Secondary endpoints examined individual event components, bleeding, gastrointestinal events, and medical costs.

### **Key Findings and Interpretations**
The trial found that clopidogrel monotherapy significantly reduced the risk of MACCE compared to aspirin monotherapy (hazard ratio [HR] 0.71, p=0.013), primarily driven by reductions in myocardial infarction rates. Both groups demonstrated similar risks for bleeding events, with no apparent difference in major bleeding. The authors suggest that clopidogrel offers enhanced ischemic protection while maintaining safety in terms of bleeding risk.

### **Strengths**
- **Robust Sample Size**: The study involved over 5500 patients, ensuring statistical power and reliability.
- **Focused Endpoint**: Choosing MACCE as the primary endpoint emphasized clinically significant outcomes.
- **Risk Stratification**: The study targeted patients with high ischemic risk, providing insights into subgroups with complex coronary profiles.

### **Limitations**
- **Open-Label Design**: The lack of masking may have introduced bias in treatment administration and adverse event reporting.
- **Population Specificity**: The trial exclusively enrolled Korean patients, which limits the generalizability of findings to other ethnic groups.
- **Unexpected Event Rates**: Lower-than-anticipated adverse event rates reduced the strength of evidence for the observed benefits.

### **Clinical Implications**
The findings support clopidogrel monotherapy as a preferable alternative to aspirin for long-term secondary prevention in PCI patients with high ischemic risk. This trial contributes to evolving guidelines and emphasizes the importance of personalized therapy strategies for patients with coronary artery disease.

Does this align with the level of analysis you were looking for? If you'd like further discussion on specific sections or methodologies, feel free to let me know!.

[02/04, 14:33]: Copilot 👆


[02/04, 14:33]asml llm: Absolutely, Salam! The methodological framework of the SMART-CHOICE 3 trial is quite sophisticated, and here's a detailed breakdown:

---

### **Study Design**
The SMART-CHOICE 3 trial was a multicenter, prospective, randomized, open-label study conducted in South Korea. The trial focused on evaluating clopidogrel versus aspirin monotherapy in patients at high risk of recurrent ischemic events after completing a standard duration of dual antiplatelet therapy (DAPT) following PCI. Importantly, the design deliberately targeted a patient population with complex coronary profiles or clinical factors associated with higher ischemic risks.

---

### **Eligibility Criteria**
The study established clear inclusion and exclusion criteria:
- **Inclusion:** Patients aged 19 or older who underwent PCI successfully with drug-eluting stents, completed the standard duration of DAPT (≥12 months for myocardial infarction or ≥6 months for other PCI indications), and exhibited complex coronary lesion characteristics or high clinical ischemic risk factors (e.g., previous myocardial infarction, diabetes).
- **Exclusion:** Those under long-term oral anticoagulant therapy, already on single antiplatelet therapy, or with contraindications to aspirin or clopidogrel. Details of these criteria were further defined in the appendix, ensuring precision in patient selection.

---

### **Randomization and Masking**
Participants were randomized in a 1:1 ratio via a web-based system using block randomization (blocks of size four). Stratification ensured balanced allocation across clinical presentations (e.g., myocardial infarction vs. other indications for PCI) and study sites. Notably, the trial was open-label, meaning participants and investigators were aware of group assignments, which might introduce biases despite efforts to minimize them.

---

### **Intervention**
After randomization, patients immediately transitioned to monotherapy with either clopidogrel (75 mg daily) or aspirin (100 mg daily). Follow-up assessments occurred regularly—6 months and 12 months after randomization and annually thereafter—to monitor adherence, adverse events, and clinical outcomes.

---

### **Event Adjudication and Bias Management**
To mitigate potential biases from the open-label design, an independent clinical event adjudication committee reviewed all reported primary and secondary events. The committee members worked in a blinded manner, ensuring the objective assessment of endpoints like myocardial infarction and major bleeding.

---

### **Endpoints**
- **Primary Endpoint:** Composite incidence of major adverse cardiac and cerebrovascular events (MACCE), including death from any cause, myocardial infarction, and stroke.
- **Secondary Endpoints:** Examined individual event components (e.g., bleeding, stent thrombosis), gastrointestinal complications, and medical costs (not included in the initial publication).

---

### **Sample Size and Statistical Rigor**
The target sample size of 5000 patients was calculated to achieve 82% statistical power for detecting a 25% lower MACCE incidence with clopidogrel compared to aspirin. This calculation assumed a base annual incidence of 4% for aspirin and 3% for clopidogrel. Due to unexpectedly low event rates, enrollment was extended beyond the original target to strengthen findings.

---

### **Analysis Approach**
Analyses were conducted primarily on an intention-to-treat basis, with supplementary per-protocol sensitivity analysis. Kaplan-Meier survival analysis estimated endpoint incidences, while Cox proportional hazards models quantified relative risks. Competing-risk analyses were also incorporated for secondary endpoints, addressing potential confounding effects like non-cardiovascular mortality.

---

### **Challenges**
The study faced methodological challenges, including:
1. **Open-Label Design**: While the primary composite endpoint minimized bias, the lack of masking might have influenced behaviors (e.g., medication initiation).
2. **Low Event Rates**: This reduced statistical strength despite the expanded sample size.
3. **Population Specificity**: Exclusively Korean participants potentially limit generalizability to other ethnic or geographic groups.

---

This trial exemplified methodological rigor, from patient stratification and outcome adjudication to addressing biases inherent in its open-label nature. Would you like me to delve deeper into the statistical methods or discuss their implications for future trials?


[02/04, 14:34]cm: Did we use the same prompt for all the LLMs?

It would be interesting to test that perhaps even using med arena who will anyways run it through all


[02/04, 14:34]asml llm: Certainly! The statistical methodology of the SMART-CHOICE 3 trial was thoughtfully designed to ensure precision and robust findings. Here's a detailed examination:

---

### **Study Hypothesis and Sample Size Calculation**
The trial hypothesized that clopidogrel monotherapy would be superior to aspirin monotherapy for reducing major adverse cardiac and cerebrovascular events (MACCE). To test this:
- The **sample size** was calculated assuming an annual MACCE incidence rate of 4% for aspirin and 3% for clopidogrel monotherapy.
- A sample size of **5000 patients** was targeted to provide 82% statistical power to detect a 25% reduction in MACCE, with a **two-sided type I error rate of 0.05**.
- The researchers anticipated a **dropout rate of 2.5%**, and the accrual period was set at **3 years**, followed by **1 year of minimum follow-up**.

Due to **unexpectedly low event rates**, the actual enrollment was extended, resulting in **5506 randomized participants**.

---

### **Data Analysis Approach**
The analyses followed an **intention-to-treat principle**, meaning all participants were analyzed based on their original group assignments, regardless of deviations or discontinuation. A **per-protocol sensitivity analysis** was also conducted, excluding participants with protocol violations, to validate the findings.

1. **Primary Endpoint Analysis**:
   - **Kaplan-Meier Method**: This non-parametric approach estimated the cumulative incidence rates for MACCE at the 3-year follow-up, allowing visualization of event timing through survival curves.
   - **Cox Proportional Hazards Model**: Used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for event risks in clopidogrel versus aspirin groups. The models were adjusted for baseline stratification factors, such as clinical presentation and study site.
   - **Proportional Hazards Assumption**: Verified using Schoenfeld residuals, ensuring that the hazard ratio remained constant over time.

2. **Secondary Endpoint Analysis**:
   - **Competing-Risk Analysis**: The Fine-Gray subdistribution hazard model was applied to assess the risk of specific secondary endpoints (e.g., cardiovascular death or myocardial infarction) while accounting for competing events, such as non-cardiovascular deaths.

3. **Type I Error Control**:
   - A **permutation test** with **5000 resampling iterations** empirically estimated the type I error rate, which was reported as 1.7%. This supported the reliability of the findings despite the lower-than-expected event rates.

---

### **Sensitivity and Subgroup Analyses**
- **Sensitivity Analyses**: Conducted for participants with complete follow-up over various durations (1, 2, and 3 years), confirming the robustness of the primary endpoint results.
- **Subgroup Analyses**: Explored treatment effects across predefined subgroups, such as age, sex, presence of diabetes, renal function, and anatomical complexity of PCI. The interaction tests examined heterogeneity in treatment effects across these subgroups.

---

### **Multiplicity and Adjustment**
- The trial did not adjust for **multiple testing**, avoiding inflation of type I error across numerous comparisons. Consequently, p-values for secondary endpoints were not reported to prevent misinterpretation.

---

### **Limitations in Statistical Design**
- **Lower Event Rates**: This reduced statistical power despite expanded enrollment. While the findings were statistically significant, the trial acknowledged the possibility of weaker evidence due to lower-than-anticipated event rates.
- **Open-Label Design**: Although efforts (like blinded event adjudication) mitigated potential biases, unmasked treatment assignments could have influenced clinical management (e.g., prescribing gastrointestinal protective medication).

---

The trial’s statistical framework exemplified meticulous planning to balance rigor, ethical considerations, and practical constraints. If you'd like further elaboration on the Kaplan-Meier survival curves or subgroup analyses, I’d be happy to discuss them!
[02/04, 14:43] Dr.Abdulsalam Med Ed Leads: Below is an in‐depth description of the study’s limitations, reflecting both the authors’ discussions and the broader methodological implications:

---

### 1. **Open-Label Design**

- **Potential for Bias:**  
  The trial was conducted in an open-label fashion, meaning that both the participants and investigators were aware of the treatment assignments. Although the primary composite endpoint (which includes death, myocardial infarction, and stroke) is objective and was adjudicated by an independent, blinded committee, this design still leaves room for bias in several areas. For example, knowledge of the treatment might have influenced the clinicians’ decisions regarding follow-up testing, use of ancillary medications (like gastrointestinal protective therapies), or even patient management strategies in the event of complications.

---

### 2. **Lower-Than-Expected Event Rates**

- **Statistical Power and Event Distribution:**  
  The study was originally powered based on an expectation of a certain annual incidence of MACE. However, the actual event rates observed were lower than anticipated. While the adjusted sample size helped to maintain statistical power, fewer events can sometimes decrease the robustness of subgroup analyses and make the interpretation of secondary endpoints more challenging.
  
- **Implications of Low Event Rates:**  
  A lower event rate also raises questions about whether the patient selection (patients who had already completed a relatively long DAPT period) may have contributed to a population at lower overall risk, thereby potentially limiting the applicability of the findings to patients with different risk profiles.

---

### 3. **Population and Generalizability Issues**

- **Single-Nation, Single-Ethnicity Enrollment:**  
  The study exclusively enrolled Korean patients. Ethnic and genetic differences can influence both the pharmacokinetics and pharmacodynamics of antiplatelet agents. For instance, variations in the CYP2C19 gene affect clopidogrel metabolism, and the prevalence of these gene variants may differ across ethnic groups. As a result, the findings may not be directly applicable to populations in other regions (such as Western or multiethnic cohorts).

- **Underrepresentation of Women:**  
  Women constituted only about 18% of the study population. This underrepresentation limits the ability to generalize the outcomes to female patients, particularly since cardiovascular disease can present and progress differently by sex.

---

### 4. **Patient Selection and Baseline Characteristics**

- **Selection Bias from Inclusion Criteria:**  
  The study focused on patients at high risk of ischemic events who had successfully completed a standard duration of DAPT. This highly selected group (including those with complex coronary lesions or a history of myocardial infarction/diabetes) might not reflect the broader spectrum of patients undergoing PCI, particularly those at lower risk or with concurrently high bleeding risk.

- **DAPT Duration Before Randomization:**  
  The median interval between the index PCI and randomization was about 17.5 months, which is longer than the standard minimum recommended duration for DAPT in many guidelines. This prolonged period may have influenced the event rate (by selecting out patients who tolerated DAPT well) and might limit the applicability of the findings to patients who discontinue DAPT earlier.

---

### 5. **Statistical Considerations Related to Multiple Comparisons**

- **Multiplicity of Endpoints:**  
  While the primary endpoint was clearly defined, multiple secondary endpoints were explored without adjustments for multiple comparisons. This approach increases the chance of a type I error (i.e., finding a significant difference by chance) when interpreting the secondary outcomes. The authors, therefore, urged caution with the p-values associated with these secondary analyses.

---

### 6. **Treatment Strategy Considerations**

- **Pre-Existing Antiplatelet Regimens:**  
  Before randomization, a high proportion of patients were already on clopidogrel-based DAPT regimens. The legacy effect of prior therapy, as well as the specific choice of antiplatelet agents before the switch to monotherapy, may have influenced the outcomes and makes it challenging to compare directly with populations in which more potent agents (e.g., ticagrelor or prasugrel) are more commonly used.

---

### **Summary**

The study's limitations include potential biases introduced by its open-label design, lower-than-expected event rates, and issues related to generalizability due to the homogeneous patient population (primarily Korean and predominantly male). Additionally, the particular patient selection (having completed a long DAPT period) and the absence of multiple testing corrections in secondary endpoints further temper the interpretation of the results. Recognizing these limitations is crucial for understanding the context in which clopidogrel monotherapy might be favored over aspirin and for guiding future research that could address these gaps in evidence.

Would you like additional details on any of these points or further discussion on how these limitations might influence clinical decision-making?

[02/04, 14:44] asml: deep thinking response of the 👆copilot


[02/04, 14:46] asml llm: The limitations of the study have several important implications on the interpretation and generalizability of its findings. Here’s a detailed breakdown:

---

### **1. Open-Label Design and Potential Bias**

Because both participants and investigators were aware of the treatment assignments, there is the possibility of performance and detection bias. Although the primary endpoint (comprising death, myocardial infarction, and stroke) is hard and was adjudicated by a blinded committee, clinicians might have altered their management—for instance, by prescribing additional protective medications for known-risk patients on aspirin. In a clinical setting, such behavioral changes could potentially dilute or exaggerate the observed differences between the treatment groups. This means that while the primary outcome is relatively robust, nuances in secondary outcomes or care practices might be influenced by the lack of blinding, thereby slightly tempering confidence in the findings.

---

### **2. Lower-Than-Expected Event Rates**

The trial was powered based on anticipated event rates that turned out to be higher than the actual observed rates. A lower event rate decreases the overall number of endpoints captured, which can impact the statistical power of the study—especially for subgroup and secondary endpoint analyses. With fewer events, the confidence intervals around the estimated effects tend to widen, reducing the precision of the estimated treatment benefits and making it more challenging to detect differences in less common outcomes. As a result, while the trial found a statistically significant lower risk of MACE with clopidogrel, the overall robustness of these findings might be somewhat attenuated.

---

### **3. Population Specificity and Generalizability**

The study exclusively enrolled Korean patients and included a predominantly male cohort. Such a homogeneous population raises questions about how applicable the results are to broader or more diverse populations. Genetic factors, such as variations in CYP2C19 polymorphisms that influence clopidogrel metabolism, may differ significantly between ethnicities. This means that while clopidogrel monotherapy appears beneficial in this population, the same magnitude—or even direction—of effect might not be observed in Western or more diverse cohorts. Additionally, underrepresentation of women limits our understanding of how these therapies perform across sexes, potentially missing important sex-based differences in response.

---

### **4. Patient Selection Criteria**

Patients in the trial had already completed a relatively long duration of DAPT (median of 17.5 months) and were deemed at high ischemic risk. This selection process tends to exclude patients who might have experienced early adverse events or bleeding issues during the DAPT period. Consequently, the study population might represent a “survivor” subset that is more tolerant to antiplatelet therapy, which could lead to an underestimation of bleeding risks or other complications. The benefits observed with clopidogrel may not extend to patients who require shorter DAPT durations or those at very high risk of bleeding, thereby limiting the applicability of the findings to all PCI patients.

---

### **5. Statistical Considerations**

The absence of adjustments for multiple testing in the analysis of secondary endpoints means that some statistically significant findings could be due to chance. While the primary endpoint was rigorously defined and analyzed, caution should be exercised when interpreting secondary outcomes because the risk of type I error (false positives) is inherently higher under these circumstances. This necessitates further studies or meta-analyses to confirm the additional benefits or harms noted in secondary endpoints.

---

### **Overall Impact on Study Findings**

In essence, these limitations suggest that while the study provides promising evidence in favor of clopidogrel monotherapy over aspirin for reducing MACE in a specific, high-risk, and relatively homogeneous population, caution is warranted when generalizing these results. The observed benefit should be interpreted in light of potential biases, a possibly underpowered detection of rarer events, and issues related to external validity. Future research—particularly studies that include more diverse populations, double-blind designs, and adaptable statistical methods to handle multiple comparisons—will be necessary to corroborate these findings and to fully understand their implications in broader clinical practice.

Would you like to explore further how these statistical and design limitations might be addressed in future research, or perhaps discuss the potential implications for clinical guidelines?

[02/04, 15:20] asml: Model B was: google/gemini-2.5-pro-exp-03-25:free gives the best response


Thematic Analysis:*

- *Coding:*
    1. Evidence-Based Medicine (EBM)
    2. Absolute Risk Reduction (ARR)
    3. Number Needed to Treat (NNT)
    4. Patient-centered care
    5. Clinical decision-making


- *Categorization:*


    1. *Evidence-Based Medicine (EBM):* The conversation emphasizes the importance of EBM in interpreting study results and making clinical decisions.

    2. *Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT):* The discussion highlights the value of ARR and NNT in understanding the magnitude of the benefit and making informed decisions.

    3. *Patient-Centered Care:* The conversation focuses on presenting study results in a patient-centered manner, using absolutist EBM framing to help patients understand the benefits and risks.

- *Learning Insights:*

    1. Evidence-Based Medicine (EBM) is crucial in interpreting study results and making clinical decisions.

    2. Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT) provide valuable insights into the magnitude of the benefit and can inform clinical decision-making.

    3. Presenting study results in a patient-centered manner, using absolutist EBM framing, can help patients understand the benefits and risks and make informed decisions.


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Wednesday, April 2, 2025

UDLCO CRH: Time to pull our act together around fetal sex determination in India?

Summary:

Problem statement: Globally fetal gender determination is easily done using maternal blood cell-free fetal DNA (CfDNA) that provides near 100% specificity and sensitivity for fetal y chromosome. Yet in India ultrasound centers and doctors are regularly made to work extra to comply with the PCPNDT act initially formulated in 1994 to prevent female foeticide.
The conversational transcripts discuss the legal and ethical implications of revealing a fetus's gender in India, particularly in the context of the Pre-Conception and Pre-Natal Diagnostic Techniques (PCPNDT) Act and questions it's current relevance in the presence of molecular biology techniques that can easily outperform ultrasound for fetal sex determination technique s. The conversation highlights the tension between the law's intention to prevent female feticide and the reality of subtle gender revelation practices. Participants also discuss the role of technology, such as chromosomal analysis of maternal blood, in gender determination and the potential consequences of revealing gender information. 

*Key Words:*

- PCPNDT Act
- Gender determination
- Female feticide
- Chromosomal analysis
- Maternal blood test
- Sex selection
CRH Critical realist heutagogy 

Conversational Transcripts:

[02/04, 15:29]hu1: Also, is it legal to reveal the gender in India even if the gender identification is done overseas?


[02/04, 17:24]hu2: The question is intriguing. Radio diagnosis cannot report the gender (and that restricts what innovations we can bring in)

However, IVF facilities are allowed to - maybe even expected to carry out Preimplantation Genetic Testing (PGT). Does any law prevent them from revealing the foetus's gender?

There are centers (at least one in LA) that claim gender selection as their expertise!

Maybe their laws are different, but isn't selection different from disclosure?


[02/04, 17:26]hu3: Scientific evolution can't be restricted...law around it needs flexibility to assure greater good


[02/04, 17:27]hu3: Genetically edited baby is not far from reality

[02/04, 18:52]hu4: The regulation of not revealing the gender is more on paper than real like several other laws in India. The fact is this is done in a very subtle manner using terminologies like "Jai Shri Ram" or "Jai Mata ji".  The sole purpose of the legislation was to prevent abortions of female foetuses. On the other hand are more social / ethical issues (pregnancy after two healthy children of the same gender?), so should population control be more important? or should parents unwilling to have a child of the same gender be forced to a pregnancy to full term when the mother has the full right to abort the baby upto 20 weeks?

[03/04, 05:22]hu5: What is an open secret is that. Using US to detect the fetal gender is no longer required. A simple Chromosomal analysis of maternal blood is enough. Positive for _y chromosome_ in 8 weeks if male


[03/04, 05:24]hu5: The reason why this act is continuing as it is good earning for the regulators. We are all appealing the reverse, announce the gender to the government for every case - and let the parents explain why they aborted


[03/04, 06:28]hu6: Yes with a high sensitivity and specificity too!👏👏



Background to the PCPNDT act toward closing access to sex determination to prevent feticide in India and China:



Background to global open access policies around sex determination:


Thematic Analysis:*

- *Coding:*
    1. Legal and ethical implications
    2. Gender determination and revelation
    3. Female feticide and sex selection
    4. Role of technology in gender determination
    5. Consequences of revealing gender information
- *Categorization:*
    1. *Legal and Ethical Frameworks:* The conversation highlights the complexities of the PCPNDT Act and its implementation.
    2. *Gender Determination and Revelation:* Participants discuss the various methods of gender determination, including chromosomal analysis of maternal blood.
    3. *Female Feticide and Sex Selection:* The conversation touches on the issue of female feticide and the role of sex selection in Indian society.
- *Learning Points:*

    1. The PCPNDT Act aims to prevent female feticide, but its implementation is complex and often subtly circumvented.
    2. Technology, such as chromosomal analysis of maternal blood, has made gender determination more accessible and accurate.
    3. Revealing gender information can have significant consequences, including the potential for sex selection and female feticide.
    4. The conversation highlights the need for a nuanced understanding of the legal, ethical, and social implications of gender determination and revelation in India.




Epilogue:

[03/04, 06:55]hu2: Health IT can play a moderator's role.


Device output can be block chained by mandatory law - and it doesn't cost much


There can be a well defined review panel, which can reveal the gender to courts in a sealed cover.


If leave is granted, mandatory social worker engagement may be enforced and MTP allowed on a case by case basis.


Challenges:


1. The review results may arrive by the time the unborn's grandkids are grown ups


2. Aftermarket modification of block chained modalities may become big business 


3. The review panel may not have enough of an incentive left, after the payables are deducted from the receivables 


My opinion - our laws may be archaic, but the problem lies elsewhere (not in the Parliament)


[03/04, 07:19]cm: Even the device output for maternal blood cell-free fetal DNA (CfDNA) to detect fetal y chromosome with 100% sensitivity and specificity? Do we have an estimate of how many such devices exists?

Posted by at No comments:

Monday, March 31, 2025

UDLCO CRH: Soulful journal club on oral semaglutide vs placebo!

Summary: Current Medical education systems that are far from globally average in many parts of the world work on promoting rote memorization and hardly ever promote critical thinking as a result of which most students once they enter the industry fall prey to simplistic big pharma influences that use relative values driven and interpreted RCT data!


The discussion on this journal club formed organically and randomly out of a group of physicians excited about the launch of a new drug hits a climax when a user points out a particular side effect that is pivoted on to explain in terms of absolute values why taking the drug is akin to trading off and bearing some distaste in the tongue (side effect), just so that they can become one with the group of (4825-191=4634) higher number of people (taking the drug oral semaglutide) that could avoid a nonfatal myocardial infarction as opposed to the lesser (4825-253=4572) number in the 
placebo group who still had the joy of taste but then 62 more of their placebo brethren developed a non fatal myocardial infarction compared to those on oral semaglutide! 

If that is interpreted as a primeval herd instinct to find safety in numbers and if we can imagine the two groups of 4825 people as wildebeests wading to cross a crocodile filled African river of metabolic syn then can we really spot the difference of 191 vs 253 missing in each group when the wildebeest cross over to the other side?

While the above provides an apparently polarised anti big pharma biased viewpoint, the same day this author discovered a new AI LLM tool from a Stanford lab called med pharma and unboxing it here: 
https://medicinedepartment.blogspot.com/2025/03/unboxing-med-arena-for-first-time.html?m=1, offered a more balanced perspective where while the LLM appreciated the absolute number world view, it hinted that we need to remember that the paper also reports relative risks (hazard ratios), which are essential for understanding proportional reductions in risk. Both perspectives are valuable.


Key words:

Big pharma Journal club influencers

Proportional risk reduction 

CRH Critical realist heutagogy 



Journal club collective conversational Transcripts:

[29/03, 19:46]wa user 1: Have a few paid links for live SOUL relay at about 1.15 am tonight.  Anyone interested pls DM me

[29/03, 19:52]wa user 2: Morning heading news plz
Breaking news

[29/03, 19:56]WA user 3 : What?
[29/03, 19:57]: Ok SOUL


[29/03, 20:08]WA user 4: 1:00 am. I have free link 😂


[29/03, 20:22]: Any last minutes guess on expected results of SOUL? Closest guess maker will get prize 🏆 from me 😊


[29/03, 20:22]u2: MI
[29/03, 20:22]: Outcome

[29/03, 20:22] group moderator gm: I hope ,you know it now

[29/03, 20:23]u2: I'm sure AK knows

[29/03, 20:24]u4: Oreyy Dada…bhogwan 😨

[29/03, 20:24]u2: I guess 14%reduction in MACE  and stroke due to sema 

or is that old news

[29/03, 20:26]u4: Your AI 🤖 didn’t work here 😂😂

[29/03, 20:28]u2: I know. It can't find out what is not leaked on the net

[29/03, 20:28]u4: If oral sema reduces MI significantly - would you prefer it over SGLT2i ?

[29/03, 20:30]gm: No

[29/03, 20:30]u4: Why not ? Due to cost ?


[29/03, 20:31]gm: Cost and tolerance issues
More confidence with SGLT2I


[29/03, 20:31] u3: In certain situations
1. If MI is the prominent risk and not HF
2. If eGFR is less than 30
3. If weight is a major concern sema I would prefer

[29/03, 20:32]u2: I prefer 

Need close look of the study

[29/03, 20:32]u4: STRIDE trial of injectable Semaglutide in PAD is being live presented at ACC now


[29/03, 20:34]u3: I guess what you are trying to say u4 is the data being presented today may reestablish sema to be a superior cardiac and cv drug over SGLT2i.


I was fortunate to attend your brilliant comparison of dapa and empa in MAHARSSDI 2025 here in Mumbai


[29/03, 20:34]u4: Did any drug reduce MI in past? If it is true it would add great value to the money with oral sema beside best Hba1C and body weight reduction amongst all anti diabetes drugs!


[29/03, 20:39]u2: Yup
[29/03, 20:39]u3: Understood where this argument is going. 

I guess at 1.20 am history is going to be created with sema

[29/03, 20:39] u4: 1.15am

[29/03, 20:40]u3: Waiting for the prize from u4🫶🫶🫶

[29/03, 20:41]u3: Just as Dapa is now a mandatory arsenal in the therapeutic armamentarium of cardiologists i guess after 1.15 am Sema will be a mandatory prescription for most cardiologists dealing with MI

[29/03, 20:41]u2: Sir me too
🙏🙏





[30/03, 08:25] u6: My humble observations:
1) Happy that MI was reduced
2) Surprised to see stroke wasn`t reduced
3) Limb events – upto 2 years no benefit – actually at one point it was worse than placebo - then all of a sudden the line diverges
4) A1C > 8 far better than < 8 (but p value for interaction not given) – so again the question arises – was better glycaemic control partially responsible for the benefits? Of course just glycaemic control on its own does not matter but still

In summary, my humble thoughts

_*Great for Sema*_
• MI reduction for the first time
• Limb events reduction for the first time
• Better in Asians (however no p value for interaction given)

*Not so great*
• No reduction in stroke
• No reduction in CKD
• No reduction in HF
• Less than 3 kg weight loss


[30/03, 08:33]gm: Thank you 🙏

[30/03, 08:33] u6: The distribution of participants who were receiving the 3-mg, 7-mg, and 14-mg doses of oral semaglutide over time is summarized in Figure S3A (but I don`t have access to it)
27% discontinued the drug so would have been interesting to know the trial product estimand


[30/03, 08:36]u1: 1. What are the anti diabetics used alongside Sema?
2. Do statin and aspirin continued as per present guidelines?

[30/03, 08:39]u6: I don`t know the exact figures but as it was a double blind randomised control trial it is expected that both groups would have equal distribution of statin and aspirin

[30/03, 08:48]u3: Here is the summary from AI


Here are the salient points from the discussion and results sections of the article, presented in point format:

**Results:**

*   The SOUL trial randomized 9650 participants aged 50 years or older with type 2 diabetes and either atherosclerotic cardiovascular disease, chronic kidney disease, or both, to receive either once-daily oral semaglutide (maximal dose 14 mg) or placebo, in addition to standard care.
*   **Oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events (MACE), the primary outcome (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), compared to placebo**. The hazard ratio was 0.86 (95% CI, 0.77 to 0.96; P = 0.006).
*   The incidence of the primary outcome was 12.0% in the oral semaglutide group and 13.8% in the placebo group, with incidence rates of 3.1 and 3.7 events per 100 person-years, respectively.
*   In a prespecified analysis of events occurring through week 156 (3 years), the absolute risk reduction was 2.0 percentage points, and the number needed to treat to prevent one event was 50.
*   The effect of oral semaglutide on the primary outcome was consistent across prespecified sensitivity analyses and most subgroups, including those defined by age, sex, body-mass index, history of cardiovascular or kidney disease, eGFR, and medication use at baseline.
*   Among the components of the primary outcome, **nonfatal myocardial infarction occurred less frequently in the oral semaglutide group** (hazard ratio, 0.74; 95% CI, 0.61 to 0.89).
*   The first confirmatory secondary outcome, major kidney disease events (a five-point composite), did not differ significantly between the two groups (hazard ratio, 0.91; 95% CI, 0.80 to 1.05; P = 0.19).
*   Due to the non-significant result for the first confirmatory secondary outcome, the subsequent confirmatory secondary outcomes (death from cardiovascular causes and major adverse limb events) were not formally tested for significance.
*   Supportive secondary outcomes showed that oral semaglutide was associated with a lower risk of a five-point composite of MACE and fatal or nonfatal myocardial infarction.
*   Oral semaglutide led to a greater reduction in mean glycated hemoglobin level and mean body weight from baseline to week 104 compared to placebo.
*   The incidence of serious adverse events was lower in the oral semaglutide group (47.9%) compared to the placebo group (50.3%; P = 0.02).
*   **Gastrointestinal disorders were more common with oral semaglutide** (5.0%) than with placebo (4.4%) and were the main reason for permanent discontinuation of the trial regimen in the oral semaglutide group.

**Discussion:**

*   **Oral semaglutide significantly reduced the risk of major adverse cardiovascular events compared to placebo** in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both. This represents a relative risk reduction of 14%.
*   This cardiovascular benefit is consistent with results reported for injectable semaglutide and other GLP-1 receptor agonists with established cardiovascular efficacy.
*   The dominant beneficial effect of oral semaglutide in SOUL was the reduction in nonfatal myocardial infarction, which differs from the PIONEER 6 trial where the dominant effect was on cardiovascular death. This difference might be related to the longer follow-up and larger sample size in SOUL.
*   The non-significant finding for major kidney disease events in SOUL contrasts with the significant kidney benefits observed with injectable semaglutide in the FLOW trial. This discrepancy could be due to differences in baseline eGFR of the study populations or the lower bioavailability of oral semaglutide compared to subcutaneous semaglutide.
*   The availability of an effective oral GLP-1 receptor agonist is relevant to patient preference for oral over injectable diabetes medications.
*   The overall safety profile of oral semaglutide in SOUL was consistent with previous trials, and no new safety signals were observed. The lower incidence of serious adverse events in the oral semaglutide group was mainly driven by fewer cardiac disorders and infections.
*   The higher rate of discontinuation in the oral semaglutide group was primarily due to gastrointestinal symptoms, which are known side effects of GLP-1 receptor agonists.
*   Strengths of the trial include its large sample size and long follow-up duration. The cardiovascular benefits appeared consistent across age subgroups and with injectable semaglutide. The cardioprotective effect was observed even with high concomitant use of other cardiovascular protective drugs like SGLT2 inhibitors.
*   Limitations of the trial include the inclusion criteria that enriched the population for cardiovascular and kidney disease, making it less representative of the general type 2 diabetes population. There was also underrepresentation of women and Black individuals in the trial. The effects of oral semaglutide on kidney-related outcomes require further clarification.

[30/03, 08:48]u3: and here is the audio podcast



[30/03, 11:59]u4: SOUL stratified on and off SGLT2i!

Another publication happened last night in circulation!



[30/03, 12:19]u4: This is 3rd publication happened last night in Diabetes Care after SOUL. MA of all 10 GLP-1RA trials conducted to date including FLOW and SOUL




[30/03, 13:17] CBBLE cable moderator cm: Thanks for sharing.

The authors list one of the limitations of their study as ecological bias (aka aggregation bias).

"in meta-regression on aggregate data, associations between average patient characteristics and the pooled treatment effect do not necessarily reflect true associations between the individual patient-level characteristics and treatment effect. 

The difference between associations of treatment effects with average patient characteristics at group level and true associations with individual patient level characteristics has been referred to as ecological fallacy or aggregation bias."



[30/03, 13:57] u4 in response to u6: 

Good summary:

Few point to note - 

1. Even more 28.5% permanently withdrew in placebo arm 

2. ⁠PP analysis/Trial product estimand showed even larger 18% reduction in primary endpoint 

3. ⁠No additional benefit or harm with or without SGLT2I on CV endpoints 

4. ⁠No analysis of kidney outcomes stratified on or off SGLT2i currently available 

5. ⁠12% insignificant stroke reduction must be read in light of lesser HTN pt and higher HF patients in SOUL compared to SUSTAIN6 

I will come with even more details tonight

[30/03, 14:01] cm : Interesting to see sulphonylurea still leading in both groups ahead of the new gen!


[30/03, 14:11] cm: From the soul nejm paper under discussion and accessible here: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2501006

"Adverse events that led to permanent discontinuation of oral semaglutide or placebo occurred 
in 749 participants (15.5%) in the oral semaglutide group and in 559 participants (11.6%) in the 
placebo group."

The 28.5% figure is from another paper?


[30/03, 14:19]u4: Adverse event and withdrawal is not same. Read full paper you will find what I wrote..😊


[30/03, 14:21]cm: Adverse events that led to permanent discontinuation definitely sounds same as withdrawal?

30/03, 14:55] u4: 1. Adverse events is one thing 
2. Adverse events leading to drug withdrawal is another thing 
3. ⁠Drug discontinued due to any cause is another but final thing 

We are saying 21.7% vs 28.5% didn’t complete the treatment in Sema vs PBO, respectively. Hope it’s clear now 😊😎

[30/03, 15:11]cm: Agree! Withdrawal and "Didn't continue treatment" are definitely not the same as per their trial definitions as there were other causes of discontinuation other than voluntary withdrawal such as getting lost to follow up (which is kind of absconding withdrawal vs LAMA withdrawal)!

[30/03, 14:24]u7: Many people get tired of not feeling the joy
of eating - some have told me that’s why they stopped, not because they did not tolerate…


[30/03, 14:34]u3 sharing more articles presumably detailing the effect of GLP1s on taste:





[30/03, 15:05] cm: As per yesterday's soulful release here:
https://www.nejm.org/doi/pdf/10.1056/NEJMoa2501006, they can still derive some joy from the fact that: by  trading off some distaste in the tongue, they can become one of the (4825-191=4634) higher number of people (because of oral sema) who could avoid a nonfatal myocardial infarction as opposed to the lesser (4825-253=4572) number in the 
placebo group who still had the joy of taste but then 62 more of their placebo brethren developed a non fatal myocardial infarction compared to those on oral sema!

That kind of sums up this entire soulful trial for me. Would be happy to stand corrected from others who have read the full paper. 🙂🙏

30/03, 20:50]u4: Somebody was asking which dose of Oral Sema in SOUL...Here is the answer. Nearly 80% were on 14 mg.


[30/03, 20:53]u2: What % of your patients tolerate 14mg?

[30/03, 20:59]u4: I hate personal experience kind wala answer


[31/03, 19:08]cm: Summarising some learning points from yesterday's soulful journal club:

The estimand here is essentially the relative risk reduction and going by a Hazard Ratio (HR) = 0.86 (95% CI: 0.77–0.96).  
  - **14% RRR** = \( 1 - 0.86 = 0.14 \) (14% is the reduction in relative risk for the oral semaglutide group).  

The trial’s primary estimand uses an **intention-to-treat (ITT) analysis**, which includes all randomized participants regardless of adherence. 

A separate **per-protocol (PP) estimand** (accounting for discontinuations) showed a larger 18% RRR, but this was not the primary estimand.

The more important learning point could be around the 👇

  - Absolute Risk Reduction (ARR) = 1.8% (12.0% vs. 13.8% event rates).

One person in this journal club emphasized **absolute differences** (e.g., 62 fewer nonfatal MIs in the semaglutide group: 191 vs. 253 events).  

  - Pharma often highlights **relative risk** (14% RRR) because it appears more impressive, while absolute risk (1.8% ARR) may seem modest.






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