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.
- *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.
[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.
- *Chewing clopidogrel group*: 92 events (death, MI, or stroke) out of 2752 patients
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.
Based on the scenario provided, here's a patient-centered breakdown using an **absolutist EBM perspective**:
92/2752 patients experienced death, MI, or stroke over 2.3 years (**3.3%** absolute risk).
128/2754 patients experienced death, MI, or stroke over 2.3 years (**4.6%** absolute risk).
1. **Absolute Risk Reduction (ARR):**
- *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):**
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.
Assuming this difference is statistically significant (e.g., p < 0.05), clopidogrel is superior for the primary endpoint.
A 1.3% ARR is modest but meaningful for a serious outcome like death/MI/stroke.
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.
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.
If you recall Trisha's commentary article on values, this will be very useful for the commentary I'm currently working on!
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:
This means that for every 76 patients given clopidogrel instead of aspirin, one primary event (death, MI, or stroke) is prevented.
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
