Evidence-Based Medicine and Critical Appraisal — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Mrs Kamala Nair is a 75-year-old woman referred to the general medicine outpatient clinic for the management of newly diagnosed non-valvular atrial fibrillation. She has a 10-year history of hypertension, a 6-year history of type 2 diabetes (HbA1c 64 mmol per mol), and stage 3b chronic kidney disease (estimated glomerular filtration rate 32 mL per minute per 1.73 m², serum creatinine 128 micromol per litre, body weight 58 kg). She had a transient ischaemic attack 14 months ago, from which she made a full recovery. Three weeks ago she fell in her garden and fractured her left distal radius, now in a cast. She lives alone and values her independence above all else. She does not smoke and does not drink alcohol. Her medications are metformin, perindopril, and amlodipine. [1]

Her CHA2DS2-VASc score is 5 (age 75, hypertension, diabetes, prior TIA, sex category female) and her HAS-BLED is 4 (hypertension, abnormal renal function, prior fall, age above 65). An echocardiogram shows a left atrial diameter of 42 mm, a left ventricular ejection fraction of 55 per cent, and no valvular disease. [1]

The registrar who saw her first documented: "High stroke risk, but the CKD and the fall make me nervous about anticoagulation. The patient is keen to avoid tablets. I have deferred the decision to the consultant." [1]

Candidate's tasks

1. Present a structured opening statement (SASPOP) and a prioritised problem list.
2. Formulate the focused PICO question that frames the decision.
3. Appraise the applicability of the pivotal direct oral anticoagulant trial evidence to Mrs Nair.
4. Compute the absolute benefit (NNT for stroke) and harm (NNH for major bleeding) for her baseline risk.
5. State the GRADE strength and quality of the recommendation.
6. Describe the shared decision-making conversation.
7. Discuss the documentation and the follow-up, and the insight into the limits of evidence-based medicine. [1]

Model opening statement and problem list

"Mrs Kamala Nair is a 75-year-old woman living independently at home, referred for the management of newly diagnosed non-valvular atrial fibrillation on a background of hypertension, type 2 diabetes, stage 3b chronic kidney disease, and a recent mechanical fall with a fractured wrist, who presents a classic evidence-based medicine problem: she is at high annual risk of ischaemic stroke (CHA2DS2-VASc 5, approximately 6 to 7 per cent), but she also has an elevated bleeding risk (HAS-BLED 4), she sits near the renal exclusion threshold of the pivotal direct oral anticoagulant trials, and her values (independence, minimal tablets) must shape the final decision. [1]

Her main problems are:

1. Non-valvular atrial fibrillation with a high annual stroke risk (CHA2DS2-VASc 5), the primary indication for the decision.
2. Stage 3b chronic kidney disease (eGFR 32), which raises the applicability question and affects the dosing and the bleeding risk.
3. A recent mechanical fall with a fractured wrist, which raises the traumatic bleeding risk and the fall-related hesitation.
4. An elevated bleeding risk (HAS-BLED 4) that must be weighed against the stroke benefit in absolute terms.
5. The need for a shared decision that integrates the evidence, the clinical judgement, and her stated preference for minimal tablets. [1]

My integrated plan is: first, to formulate the focused PICO question; second, to appraise the applicability of the pivotal DOAC evidence with particular attention to the renal and fall caveats; third, to compute the absolute benefit (NNT for stroke) and harm (NNH for major bleeding) for her baseline risk; fourth, to state the GRADE strength and quality of the recommendation; fifth, to share the decision with Mrs Nair in plain language using natural frequencies; and sixth, to document the reasoning and the monitoring plan. The overarching principle is that the evidence informs the estimate of effect, my clinical expertise adjusts it for the individual, and her values shape the final decision [1]."

The focused PICO question

"The focused PICO question is: in a 75-year-old woman with non-valvular atrial fibrillation (CHA2DS2-VASc 5), stage 3b chronic kidney disease (eGFR 32) and a recent mechanical fall (Population), does apixaban at a renal-adjusted dose (Intervention), compared with warfarin or no anticoagulation (Comparator), reduce the composite of ischaemic stroke or systemic embolism (Outcome, the benefit) without an unacceptable increase in major bleeding or intracranial haemorrhage (Outcome, the harm), over a one-year horizon, and in keeping with her stated preference to remain independent? A precise PICO makes the search tractable, the eligibility criteria explicit, and the applicability judgement structured." [1]

Appraisal of applicability

"The pivotal apixaban trial demonstrated a reduction in stroke or systemic embolism and a lower rate of major bleeding (including intracranial haemorrhage) compared with warfarin. I appraise its applicability to Mrs Nair using the third section of the CASP randomised controlled trial checklist — will the results help my patients? Two applicability concerns arise [1][3].

First, the renal threshold. The trial excluded patients with an eGFR below 25 mL per minute; Mrs Nair at 32 is just inside the eligibility threshold. The relative risk reduction for stroke is consistent across the renal subgroups, so the relative effect can be applied; what changes is the absolute benefit, because her baseline risk is high, and the dosing, because the renal adjustment criteria (age 75 or above, weight 60 kg or below, creatinine 133 or above) — Mrs Nair meets age and weight, so she qualifies for the reduced dose of 2.5 mg twice daily. The marginal renal function increases the risk of accumulation and I would monitor the renal function every 6 to 12 months. [1]

Second, the fall. The trial did not specifically capture patients with recurrent mechanical falls. The presumed safety concern about anticoagulation in fallers is not supported by the evidence — the stroke-prevention benefit persists in fallers, and the choice of apixaban over warfarin itself mitigates the bleeding concern because apixaban's intracranial haemorrhage rate is lower. I would address the modifiable fall risk in parallel (a physiotherapy referral, a home-safety assessment, a medication review for sedating drugs). [1]

My judgement is that the trial evidence is applicable to Mrs Nair with these two caveats, and that the relative effect can be applied while the absolute numbers are individualised." [1]

Absolute benefit and harm for her baseline risk

"The CHA2DS2-VASc of 5 gives an estimated annual stroke risk of approximately 6 to 7 per cent without anticoagulation. Apixaban reduces ischaemic stroke or systemic embolism by approximately 80 per cent versus no therapy. The absolute risk reduction is therefore approximately 6.5 per cent multiplied by 0.80, equal to approximately 5 per cent per year; the NNT is 1 divided by 0.05, approximately 20 — about 20 patients like Mrs Nair must be treated for a year to prevent one stroke. [1]

Against this, her major bleeding risk on apixaban is elevated by the CKD and the fall to approximately 2 to 3 per cent per year, with an NNH for a major bleed of approximately 33 to 50, and a much smaller intracranial haemorrhage risk (below 0.5 per cent per year, and lower with apixaban than warfarin). The balance favours anticoagulation: a stroke prevented for every 20 treated, against a major bleed for every 33 to 50 treated. The clinical point is that the NNT and the NNH are properties of the drug applied to a patient with a defined baseline risk, not properties of the drug alone [1]."

GRADE strength and quality

"The GRADE rating for apixaban versus warfarin or no therapy for stroke prevention in atrial fibrillation is a strong recommendation on high-quality evidence [2]. The evidence starts at high quality (large, well-conducted randomised controlled trials), with no serious risk of bias, no serious inconsistency, no serious imprecision. There is a mild indirectness concern from the renal threshold and the fall history, but the relative effect is consistent across the renal and elderly subgroups, so the indirectness does not downgrade the quality below high. The recommendation is strong because the desirable effect (a disabling stroke prevented, NNT 20) clearly outweighs the undesirable effect (a major bleed, NNH 33 to 50, with apixaban's lower intracranial haemorrhage rate). The strength means I can offer anticoagulation as the default, while sharing the decision because of the individual considerations."

The shared decision-making conversation

"I would hold a structured conversation with Mrs Nair, ideally with her son or a support person present if she wishes. First, I establish her understanding and her priorities — she values her independence above all, she has had a TIA which she recovered from, and she is keen to avoid tablets. Second, I present the numbers in plain language and natural frequencies: without treatment, about 6 or 7 in 100 people like her would have a stroke this year; with apixaban, that falls to about 1 or 2 in 100 — so for every 20 people treated, one stroke is prevented. Against that, about 2 or 3 in 100 would have a major bleed, and a smaller number (less than 1 in 200) a bleed in the brain. I explain that I have chosen apixaban over warfarin because it has a lower rate of brain bleeding, which matters given her fall, and that the dose is reduced because of her age, her weight and her kidney function. [1]

I address the fall directly: a fall does not remove the stroke risk, and the evidence does not support withholding anticoagulation in fallers; I am addressing the fall risk in parallel with physiotherapy and a medication review. I address the tablets: apixaban is taken twice a day, does not require the blood-test monitoring that warfarin does, and has no food interactions. I invite her to weigh the benefit (a stroke prevented, protecting her independence) against the harm (a bleed) and the burden (twice-daily tablets), and I support whichever decision she reaches. If she is unsure, I offer her time and a follow-up appointment. The principle is that EBM integrates evidence with patient values; the evidence informs the estimate, and the patient shapes the decision." [1]

Documentation and follow-up

"I document the focused PICO question, the trial evidence and its applicability (with the renal and fall caveats explicitly named), the computed NNT and NNH for her baseline risk, the GRADE strength and quality, the conversation and her values, the decision she reaches, and the monitoring plan (renal function every 6 to 12 months, a blood count, an adherence and bleeding review, and a planned review of the decision if her circumstances change). If she elects to start apixaban, I prescribe the renal-adjusted dose, I arrange the follow-up blood tests, and I give her written information. If she elects to decline, I document the capacity assessment (she understands the stroke risk, the benefit, the harm, and the consequences of declining; she retains and weighs the information and communicates a clear decision), I optimise the modifiable risk factors, I continue the doctor-patient relationship, and I offer to revisit the decision at any time. [1]

The insight is that evidence-based medicine is a continuous cycle of ask, acquire, appraise, apply, assess [1], and that the assessment step — the scheduled review of the outcome and the decision — is what closes the loop. The discipline of EBM is not to apply the trial mechanistically but to integrate the best evidence with clinical expertise and the patient's values, to name the uncertainty, and to share the decision. Mrs Nair's case is a reminder that the patient in front of us is never the average patient in the trial; the art of medicine is to bridge that gap with judgement and with conversation."