# Clinical Cases: Medical Research Methodology

## Case 1: Interpreting a Randomized Controlled Trial

### Patient Presentation
**Demographics:** 62-year-old female retired nurse

**Chief Complaint:** "I read about a new blood pressure medication in a study and I want to know if I should switch."

**History of Present Illness:**
A 62-year-old woman with a 12-year history of essential hypertension presents to her primary care physician requesting a medication change. She brings a printed copy of a recently published randomized controlled trial (RCT) from a major medical journal. The study compared a novel angiotensin receptor-neprilysin inhibitor (ARNI) to standard ACE inhibitor therapy for primary hypertension, concluding that the ARNI reduced cardiovascular events by 18% (HR 0.82, 95% CI 0.71-0.95, p=0.008).

The patient's blood pressure has been well-controlled on her current regimen of amlodipine 5 mg and lisinopril 20 mg daily, with clinic readings averaging 128/78 mmHg. She has no history of heart failure, which is the only current FDA-approved indication for the ARNI medication. She is concerned because her father died of a myocardial infarction at age 70.

The physician reviews the study with the patient and identifies several methodological issues: the trial was industry-funded, the primary endpoint was a composite of MI, stroke, cardiovascular death, and heart failure hospitalization (with heart failure hospitalization driving most of the benefit), the study population had a mean age of 71 with 68% having pre-existing cardiovascular disease, and 23% of participants in the ARNI arm discontinued the medication due to symptomatic hypotension.

**Past Medical History:**
- Essential hypertension (12 years)
- Hyperlipidemia
- Osteoporosis
- No history of heart failure, MI, or stroke

**Medications:**
- Amlodipine 5 mg daily
- Lisinopril 20 mg daily
- Atorvastatin 20 mg daily
- Calcium/Vitamin D supplement
- Alendronate 70 mg weekly

**Social History:**
- Retired nurse, health-literate
- Non-smoker, minimal alcohol
- Walks 30 minutes daily
- Married, supportive home environment

**Family History:**
- Father: MI at age 70 (fatal)
- Mother: hypertension, alive at 84
- Sister: type 2 diabetes

### Physical Examination
- **Vital Signs:** BP 126/76 mmHg, HR 68 bpm, RR 14/min, Temp 36.7°C, SpO2 99% on room air
- **General:** Well-appearing, healthy female in no distress
- **Cardiovascular:** Regular rate and rhythm, no murmurs, no S3 or S4, JVP normal
- **Lungs:** Clear bilaterally
- **Extremities:** No edema, pulses intact

### Workup and Results

**Laboratory Studies:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| BMP | Normal | - |
| Creatinine | 0.8 mg/dL | 0.6-1.2 mg/dL |
| Potassium | 4.2 mEq/L | 3.5-5.0 mEq/L |
| LDL cholesterol | 92 mg/dL | <100 mg/dL |
| HbA1c | 5.6% | <5.7% |
| BNP | 22 pg/mL | <100 pg/mL |
| Urine albumin/creatinine | 12 mg/g | <30 mg/g |

**Critical Appraisal of the Published RCT:**
| Appraisal Domain | Finding | Concern Level |
|---|---|---|
| Randomization | Computer-generated, allocation concealed | Low |
| Blinding | Double-blind, matching placebo | Low |
| Sample size | N=8,400 (powered for composite endpoint) | Low |
| Funding source | Pharmaceutical manufacturer of ARNI | Moderate |
| Primary endpoint | Composite (MI, stroke, CV death, HF hospitalization) | Moderate |
| Component analysis | HF hospitalization drove 72% of composite benefit | High |
| Study population | Mean age 71, 68% with pre-existing CVD | High (external validity) |
| Discontinuation rate | 23% in ARNI arm (hypotension) vs. 9% control | High |
| Absolute risk reduction | 2.3% over 4.2 years | Moderate |
| NNT | 44 over 4.2 years | Moderate |

### Clinical Image

![RCT Critical Appraisal Framework](case_01_image.jpg)

*Diagram illustrating key elements of critical appraisal for randomized controlled trials, including assessment of internal validity, external validity, and clinical significance versus statistical significance. Source: Educational illustration.*

### Diagnosis
**Well-Controlled Hypertension on Current Therapy; Published RCT Not Applicable to Patient's Clinical Profile**

**Key Diagnostic Criteria:**
- Patient's BP well-controlled at 126/76 mmHg on current regimen
- Study population differs significantly from patient (older, pre-existing CVD)
- Composite endpoint driven by heart failure hospitalization; patient has no heart failure
- High discontinuation rate (23%) suggesting poor tolerability
- Industry-funded trial with potential bias in endpoint selection

### Treatment Plan
1. Continue current antihypertensive regimen (amlodipine 5 mg + lisinopril 20 mg)
2. No medication change warranted based on this trial's applicability to her clinical profile
3. Explain concepts of external validity, composite endpoints, and absolute vs. relative risk reduction
4. Discuss that a 18% relative risk reduction translates to a 2.3% absolute risk reduction (NNT 44)
5. Reinforce importance of modifiable risk factor management (exercise, diet, lipid control)
6. Monitor for future studies specifically enrolling primary prevention hypertension populations
7. Annual cardiovascular risk reassessment

### Key Learning Points
- Relative risk reduction (18%) often appears more impressive than absolute risk reduction (2.3%); always calculate both when evaluating trial results
- Composite endpoints can mask which components drive the overall result; component analysis is essential
- External validity (generalizability) must be assessed: applying trial results from high-risk secondary prevention populations to low-risk primary prevention patients may be inappropriate
- Industry funding does not invalidate a trial but warrants scrutiny of endpoint selection, comparator choice, and reporting of adverse effects
- Number needed to treat (NNT) provides a clinically intuitive measure of treatment benefit that aids shared decision-making

---

## Case 2: Understanding Number Needed to Treat

### Patient Presentation
**Demographics:** 58-year-old male accountant

**Chief Complaint:** "My cardiologist wants to add another medication and I want to understand if it's really worth it."

**History of Present Illness:**
A 58-year-old male with a history of a non-ST elevation myocardial infarction (NSTEMI) 8 months ago, treated with percutaneous coronary intervention (PCI) and drug-eluting stent to the left anterior descending artery, presents for a second opinion regarding his medication regimen. His cardiologist has recommended adding low-dose rivaroxaban (2.5 mg BID) to his existing dual antiplatelet therapy (DAPT), citing the COMPASS trial, which demonstrated a reduction in the composite of cardiovascular death, stroke, or MI (HR 0.76, p<0.001).

The patient is an accountant and is analytically minded. He wants to understand the absolute benefit of adding rivaroxaban versus the bleeding risk. He is particularly concerned because he developed a GI bleed requiring hospitalization while on DAPT alone 3 months post-MI, which resolved after Helicobacter pylori eradication and PPI therapy.

His cardiologist provided the following data from the COMPASS trial: the composite MACE endpoint occurred in 5.4% of the rivaroxaban + aspirin group versus 7.0% of the aspirin-alone group over a mean follow-up of 23 months. Major bleeding occurred in 3.1% of the combination group versus 1.9% of the aspirin-alone group.

**Past Medical History:**
- NSTEMI (8 months ago, PCI with DES to LAD)
- Upper GI bleed (3 months post-MI, H. pylori-related)
- Type 2 diabetes mellitus
- Hyperlipidemia
- Peripheral arterial disease (ABI 0.82 bilaterally)

**Medications:**
- Aspirin 81 mg daily
- Clopidogrel 75 mg daily (planned to continue for 12 months total post-PCI)
- Atorvastatin 80 mg daily
- Metformin 1000 mg BID
- Pantoprazole 40 mg daily
- Metoprolol succinate 50 mg daily
- Lisinopril 10 mg daily

**Social History:**
- Accountant, works full-time
- Non-smoker (quit 8 months ago at time of MI, 25 pack-year history)
- No alcohol use (stopped after GI bleed)
- Married, two adult children

**Family History:**
- Father: coronary artery disease, CABG at age 63
- Mother: type 2 diabetes, alive at 82

### Physical Examination
- **Vital Signs:** BP 122/74 mmHg, HR 62 bpm, RR 14/min, Temp 36.8°C, SpO2 98% on room air
- **General:** Well-appearing male, mildly anxious
- **Cardiovascular:** Regular rate and rhythm, S1/S2 normal, no murmurs or gallops
- **Lungs:** Clear bilaterally
- **Abdomen:** Soft, non-tender, no organomegaly, healed midline scar from prior EGD
- **Extremities:** Diminished dorsalis pedis pulses bilaterally, no ulcers, hair loss on bilateral lower legs

### Workup and Results

**Laboratory Studies:**
| Test | Result | Reference Range |
|------|--------|-----------------|
| Hemoglobin | 13.1 g/dL | 13.5-17.5 g/dL |
| Platelets | 224,000/µL | 150,000-400,000/µL |
| INR | 1.0 | 0.9-1.1 |
| Creatinine | 1.0 mg/dL | 0.7-1.3 mg/dL |
| eGFR | 78 mL/min | >60 mL/min |
| HbA1c | 7.1% | <7.0% |
| LDL | 58 mg/dL | <70 mg/dL (post-MI) |
| Fecal occult blood | Negative | Negative |
| H. pylori stool antigen | Negative | Negative |

**NNT/NNH Analysis of COMPASS Trial Data:**
| Metric | Calculation | Result |
|---|---|---|
| Absolute risk reduction (MACE) | 7.0% - 5.4% | 1.6% |
| NNT to prevent one MACE event | 1/0.016 | 63 over 23 months |
| Absolute risk increase (major bleeding) | 3.1% - 1.9% | 1.2% |
| NNH for one major bleed | 1/0.012 | 84 over 23 months |
| Net clinical benefit | NNT vs NNH ratio | Marginal (63 vs 84) |

### Clinical Image

![NNT vs NNH Visual Comparison](case_02_image.jpg)

*Educational diagram comparing Number Needed to Treat (NNT) and Number Needed to Harm (NNH) using icon arrays to visually represent the absolute benefit and risk of adding anticoagulation to antiplatelet therapy in secondary cardiovascular prevention. Source: Educational illustration.*

### Diagnosis
**Post-MI Patient on DAPT with Peripheral Arterial Disease, History of GI Bleeding; Considering Addition of Low-Dose Rivaroxaban Based on COMPASS Trial Evidence**

**Key Diagnostic Criteria:**
- Established atherosclerotic cardiovascular disease (post-MI + PAD)
- COMPASS trial-eligible population
- History of GI bleeding increases individual bleeding risk above trial average
- NNT of 63 vs NNH of 84 suggests marginal net clinical benefit at population level
- Individual risk-benefit ratio likely unfavorable given GI bleed history

### Treatment Plan
1. **Decision:** Defer addition of rivaroxaban at this time given history of GI bleeding, which places patient at higher individual bleeding risk than trial population
2. Continue DAPT (aspirin + clopidogrel) for total 12 months post-PCI, then transition to aspirin monotherapy
3. Continue PPI therapy indefinitely given GI bleed history and ongoing antiplatelet use
4. Reassess rivaroxaban addition after completing DAPT transition to aspirin alone (net bleeding risk may be lower)
5. Optimize other modifiable risk factors: HbA1c to <7%, continued smoking cessation, PAD management with supervised exercise program
6. Annual fecal occult blood testing and low threshold for repeat EGD if symptoms recur
7. Shared decision-making discussion documented in medical record

### Key Learning Points
- NNT (Number Needed to Treat) represents how many patients must be treated for one additional patient to benefit; lower NNT indicates greater treatment effect
- NNH (Number Needed to Harm) represents how many patients must be treated before one additional patient is harmed; higher NNH indicates better safety
- Comparing NNT and NNH provides a framework for evaluating the net clinical benefit of a therapy (ideal: NNT much lower than NNH)
- Individual patient risk factors (such as prior GI bleed) may shift the personal risk-benefit ratio away from population-level trial results
- Presenting absolute risk data and NNT/NNH facilitates shared decision-making and respects patient autonomy

---

## Case 3: Evaluating Systematic Review Quality

### Patient Presentation
**Demographics:** 45-year-old female primary care physician

**Chief Complaint:** "A systematic review says we should be screening all adults for depression annually, but I'm not sure the evidence supports this."

**History of Present Illness:**
A 45-year-old primary care physician attends a departmental journal club where a recently published systematic review and meta-analysis is presented. The review concludes that universal annual depression screening in primary care reduces depression severity at 6 months (standardized mean difference -0.32, 95% CI -0.48 to -0.16, p<0.001) and recommends implementation in all primary care settings.

The physician is skeptical because she has noticed that her practice already uses the PHQ-2 as a screening tool, and she has observed that many patients who screen positive do not follow through with recommended treatment. She wants to critically evaluate the systematic review before changing her practice's screening interval from the current "opportunistic" approach to a mandated annual protocol.

Upon detailed review, she identifies several methodological concerns: the search strategy was limited to two databases (PubMed and PsycINFO) and excluded non-English publications, the included studies had heterogeneous screening tools (PHQ-9, BDI-II, CES-D, HADS), only 4 of 12 included studies were RCTs (the remainder were observational), the I² statistic was 74% indicating substantial heterogeneity, no funnel plot or Egger's test for publication bias was reported, and the GRADE certainty of evidence was not assessed.

**Past Medical History:**
- Not applicable (physician is the evaluator, not the patient)

**Medications:**
- Not applicable

**Social History:**
- Not applicable

**Family History:**
- Not applicable

### Physical Examination
- Not applicable (this is a research methodology case)

### Workup and Results

**Systematic Review Quality Assessment (AMSTAR-2 Checklist):**
| AMSTAR-2 Domain | Assessment | Rating |
|---|---|---|
| PICO research question | Clearly defined | Adequate |
| Protocol registered a priori | No registration found (PROSPERO not mentioned) | Critical flaw |
| Literature search strategy | Only 2 databases; no grey literature; English only | Critical flaw |
| Study selection in duplicate | Yes, two reviewers with kappa reported | Adequate |
| Data extraction in duplicate | Yes | Adequate |
| Excluded studies listed with reasons | Only broad categories provided | Minor flaw |
| Included study descriptions | Adequate PICO descriptions | Adequate |
| Risk of bias assessment | Cochrane RoB for RCTs, but no tool for observational studies | Critical flaw |
| Meta-analysis methods appropriate | Random effects model used, but mixing RCTs and observational | Critical flaw |
| Publication bias assessed | Not reported | Critical flaw |
| Heterogeneity explored | I²=74% noted but not adequately explored via subgroup/sensitivity analysis | Critical flaw |
| Conflicts of interest | Lead author consultancy with screening tool manufacturer disclosed | Moderate concern |
| GRADE assessment | Not performed | Critical flaw |

**Meta-Analysis Statistical Summary:**
| Parameter | Value | Interpretation |
|---|---|---|
| Pooled SMD | -0.32 | Small-to-moderate effect |
| 95% CI | -0.48 to -0.16 | Statistically significant |
| I² heterogeneity | 74% | Substantial heterogeneity |
| Number of studies | 12 | - |
| RCTs included | 4 of 12 | Majority observational |
| Total participants | 14,832 | Adequate sample |
| Prediction interval | -0.71 to +0.07 | Crosses null -- true effect uncertain |

### Clinical Image

![Systematic Review Quality Assessment](case_03_image.jpg)

*Flowchart diagram illustrating the AMSTAR-2 critical appraisal tool for evaluating systematic review quality, highlighting the distinction between critical and non-critical domains and their impact on overall confidence ratings. Source: Educational illustration.*

### Diagnosis
**Critically Low-Quality Systematic Review with Multiple Methodological Flaws; Insufficient Evidence to Change Screening Practice**

**Key Diagnostic Criteria:**
- Seven critical flaws identified on AMSTAR-2 assessment (overall rating: critically low confidence)
- No protocol pre-registration
- Inadequate search strategy (only 2 databases, English-only)
- Mixing of RCTs and observational studies in meta-analysis without appropriate sensitivity analysis
- Substantial unexplored heterogeneity (I²=74%)
- No publication bias assessment
- No GRADE evidence certainty rating
- Prediction interval crosses the null, suggesting the true effect may include no benefit

### Treatment Plan
1. **Practice decision:** Do not change current opportunistic depression screening protocol based on this systematic review alone
2. Search for higher-quality systematic reviews on the same topic (e.g., USPSTF systematic evidence review)
3. Evaluate the USPSTF Grade B recommendation for depression screening, which is based on a more rigorous evidence synthesis
4. If adopting annual screening, ensure adequate follow-up infrastructure (counseling access, psychiatry referral, care coordination)
5. Conduct local quality improvement analysis: What percentage of PHQ-2-positive patients in the practice currently receive appropriate follow-up?
6. Present journal club critique findings to the department with AMSTAR-2 assessment results
7. Advocate for evidence-based guidelines to inform practice changes rather than individual published reviews

### Key Learning Points
- AMSTAR-2 is the validated tool for critical appraisal of systematic reviews; it distinguishes critical from non-critical methodological flaws
- A statistically significant meta-analysis result does not guarantee high-quality evidence; the underlying methodology determines confidence in the findings
- The prediction interval, unlike the confidence interval, accounts for between-study heterogeneity and provides a range of plausible treatment effects in future settings
- Mixing RCTs and observational studies in meta-analysis without sensitivity analysis inflates confidence in findings that may be driven by confounding
- Publication bias assessment (funnel plots, Egger's test) is essential because small negative studies are less likely to be published, inflating pooled effect estimates