1. Article Format and Type

This article is an interactive clinical decision format belonging to NEJM’s ‘Clinical Decisions’ series. This format is presented in a structure where two experts defend different positions assigned by the editors based on a real patient case, after which readers can express their opinions. The format does not prescribe a clear ‘correct answer’; the goal is to improve the decision-making processes of clinicians and reveal the distribution of opinions within the medical community.

Features of the Format

• Realistic, context-rich clinical case presentation
• Two experts defend assigned positions (debate format)
• Community opinion is formed via a reader poll
• Editorial independence is maintained; no single option is declared ‘correct’

2. Clinical Case Summary

A 75-year-old male patient presents for routine follow-up. His physical activity is limited due to chronic joint pain; this situation is of critical importance regarding both his cardiovascular risk profile and medication tolerability.

2.1. Patient’s Baseline Characteristics

3. Clinical Decision Options

Two experts have been assigned by the editors to advocate for different treatment targets. Below are the core arguments of both positions presented comparatively.

3.1. Option 1: SBP < 120 mmHg Target 

Advocate: Paul K. Whelton, M.B., M.D. (Tulane University, Public Health)

• Large-scale meta-analysis: A <120 target reduces major CVD events by 18% and all-cause mortality by 13% compared to a <140 mmHg target.
• Associated with better cognitive function and a 15% lower risk of dementia (He 2025, Nature Medicine).
• Similar CVD protection was achieved in patients with orthostatic hypotension (Juraschek 2023, JAMA).
• Single-pill combination regimens (dual/triple) increase treatment adherence and provide targeted BP reduction.
• Isometric resistance exercises (wall sits, yoga) can lower SBP by >8 mmHg without putting a load on the joints.
• NSAID use only increases SBP by <5 mmHg; it remains at a manageable level.

3.2. Option 2: SBP < 140 mmHg Target 

Advocate: Clinton B. Wright, M.D. (NINDS / NIH, Bethesda)

• The patient’s current BP value is within the target range of many national and international guidelines; <120 mmHg is only recommended in Canadian and Australian guidelines.
• The SPRINT trial was stopped early, and the number of participants at this patient’s BP level is insufficient for a definitive comparison.
• Although the diagnostic threshold for orthostatic hypotension (20 mmHg) is not met, the possibility of autonomic dysfunction exists; further diagnostic evaluation is required.
• BP variability and hypotensive episodes are associated with cognitive decline, which could increase with intensive treatment (Zhang 2025, Hypertension).
• Patients with neurogenic orthostatic hypotension have been underrepresented in existing studies.
• Diagnostic steps such as ambulatory BP monitoring and the Valsalva maneuver should be completed first.

4. Core Evidence Base

5. Alignment with Guidelines

Important Guideline Note: The 2025 AHA/ACC guideline recommends a <130/80 mmHg target for all older adults with a 10-year ASCVD risk >10%. This value forms a middle ground between the two options discussed in the article and is not directly compared due to the constraints of the editorial format.

6. Orthostatic Hypotension: Critical Diagnostic Evaluation

The most nuanced debate of the article shapes around orthostatic hypotension. The patient remains below the technical diagnostic threshold (>20 mmHg drop), but clinical findings suggest autonomic dysfunction.

6.1. Diagnostic Algorithm (Wright’s Suggestion)

• 10 minutes supine position → standing up → 3 minutes BP and heart rate measurement
• Valsalva maneuver: slow BP recovery, no compensatory tachycardia in neurogenic failure
• 24-hour ambulatory BP monitoring: investigation of nocturnal BP and ‘non-dipping’ pattern
• Symptom inquiry: heat intolerance, postprandial dizziness, neck pain (‘coat hanger’ pattern), olfactory impairment
• Rhythm monitoring for cardiac arrhythmias (e.g., atrial fibrillation)

6.2. Comparison of Both Experts’ Evaluations

7. Scientific Evaluation of the Article

7.1. Strengths

• Published in a high-impact, peer-reviewed journal; the Clinical Decisions series is one of NEJM’s most respected formats.
• Both experts base their arguments on current, high-evidence-level literature (RCTs, meta-analyses, 2025 guidelines).
• The clinical case is realistic and context-rich: multiple comorbidities, polypharmacy, elderly patient profile.
• Editorial independence is preserved; no position is explicitly declared ‘correct’.
• The reader participation mechanism reveals the true distribution of opinions within the clinical community.

7.2. Limitations and Methodological Notes

• The debate format forces experts to defend an assigned position; this may not fully reflect genuine clinical judgment.
• The SPRINT trial lacked sufficient statistical power in the subgroup close to this patient’s baseline BP value.
• A third option (e.g., <130 mmHg) was not presented; whereas the current AHA/ACC guideline dictates this.
• Patients with neurogenic orthostatic hypotension were excluded from most studies; there is no specific evidence for this population.
• Both experts cite some of their own studies or those of close colleagues (potential conflict of interest with limited impact).

8. Overall Evaluation and Conclusion

This article successfully summarizes the real clinical tension between intensive blood pressure control and safe treatment balance in hypertension management. The arguments of both experts are consistent with the literature and proceed through a dilemma frequently encountered in clinical practice.

Whelton’s position argues that population-level cardiovascular benefit outweighs individual safety concerns. Wright, on the other hand, emphasizes that this patient’s atypical autonomic profile may fall outside standard treatment protocols and requires a more comprehensive diagnostic evaluation. Both arguments are scientifically defensible.

Editor’s Note:

• Clinical Conclusion: The <130/80 mmHg target recommended by the 2025 AHA/ACC guideline forms a practical middle ground between both options. An individualized approach for this patient should include a combination of a careful BP titration plan, ambulatory monitoring, and exercise rehabilitation.
• Evidence Gap: Prospective RCTs investigating optimized BP targets for older hypertensive patients with neurogenic orthostatic hypotension are needed.

9. References

1. Whelton PK, O’Connell S, Mills K, He J. Evolution in the targets for blood pressure control. Curr Opin Nephrol Hypertens 2026;35:141-9.
2. Wright JT Jr, Whelton PK, Johnson KC, et al. SPRINT revisited: updated results and implications. Hypertension 2021;78:1701-10.
3. He J, Zhao C, Zhong S, et al. Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial. Nat Med 2025;31:2054-61.
4. Juraschek SP, Hu JR, Cluett JL, et al. Orthostatic hypotension, hypertension treatment, and cardiovascular disease: an individual participant meta-analysis. JAMA 2023;330:1459-71.
5. Edwards JJ, Deenmamode AHP, Griffiths M, et al. Exercise training and resting blood pressure: a large-scale pairwise and network meta-analysis of randomised controlled trials. Br J Sports Med 2023;57:1317-26.
6. Jones DW, Ferdinand KC, Taler SJ, et al. 2025 AHA/ACC guideline for the prevention, detection, evaluation and management of high blood pressure in adults. Hypertension 2025 (Epub ahead of print).
7. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
8. Duval GT, Raud E, Gohier H, Dramé M, Tabue-Teguo M, Annweiler C. Orthostatic hypotension and cognitive impairment: systematic review and meta-analysis of longitudinal studies. Maturitas 2024;185:107866.
9. Zhang W, Redline S, Viswanathan A, et al. Hypotensive episodes on 24-hour ambulatory blood pressure and cognitive function: insights from the SPRINT study. Hypertension 2025;82:627-37.

Venous thromboembolism (VTE) is considered the third most common cause of cardiovascular death worldwide after myocardial infarction and stroke. Its incidence in the general population is approximately 1–2 per 1000 people annually and increases significantly with age.

Anticoagulation for at least 3 months is the standard treatment approach for acute VTE, and in recent years direct oral anticoagulants (DOACs) have become widely used in clinical practice. In particular, apixaban and rivaroxaban have become the two most commonly preferred agents in the treatment of acute pulmonary embolism and deep vein thrombosis.

However, until now, an important clinical question remained unanswered:

Is there a real difference in bleeding risk between apixaban and rivaroxaban?

An important study seeking to answer this question was published in the New England Journal of Medicine in 2026: the COBRRA Trial.

COBRRA Trial: Design

The COBRRA trial was an international, randomized, prospective clinical study.

• 2760 patients were included in the study
• Patients were randomized 1:1 into two groups
• Study population:
  • symptomatic pulmonary embolism
  • or proximal deep vein thrombosis

The treatment protocol was as follows:

Apixaban Group

• 7 days: 10 mg twice daily
• Afterwards: 5 mg twice daily

Rivaroxaban Group

• 21 days: 15 mg twice daily
• Afterwards: 20 mg once daily

The follow-up period was planned as 3 months.

The primary endpoint of the study was: Clinically relevant bleeding

This endpoint included the following two conditions:

• Major bleeding
• Clinically relevant non-major bleeding (according to ISTH criteria)

Main Results of the Study

Toplam 2760 hasta randomize edildi.

Klinik olarak anlamlı kanama oranları:

These results were statistically significant:

Relative risk: 0.46 (95% CI 0.33–0.65, p<0.001)

In other words: The bleeding risk was approximately 54% lower with apixaban.

All-cause mortality was quite low:

• Apixaban: 0.1%
• Rivaroxaban: 0.3%

Clinical Significance

This study is important from several perspectives.

1. First Direct Comparative Study

Until now, most DOAC studies were based on comparisons with warfarin.
There had been no direct randomized comparison between apixaban and rivaroxaban.

The COBRRA trial filled this gap.

2. Difference in Safety Profile

While both drugs are considered effective in preventing recurrent thromboembolism, this study demonstrates a clear advantage in favor of apixaban regarding bleeding safety.

3. Possible Impact on Clinical Practice

These results may influence treatment selection especially in the following patient groups:

• elderly patients
• patients at high bleeding risk
• those receiving concomitant antiplatelet therapy
• patients with limited renal function

Will the Guidelines Change?

Current international guidelines generally did not recommend a clear superiority among DOACs. The reason was the lack of direct comparative studies.

Since the COBRRA trial filled this gap, it may provide data in the future that could influence DOAC preference rankings in guidelines such as:

• European Society of Cardiology (ESC)
• American College of Chest Physicians (ACCP)
• American Society of Hematology (ASH)

Conclusion

The COBRRA trial is an important randomized study directly comparing two widely used DOAC agents in the treatment of acute venous thromboembolism.

The main message of the study is clear:

Compared with rivaroxaban, apixaban demonstrated similar efficacy while showing a significantly lower risk of clinically relevant bleeding.

This finding may lead us to reconsider treatment selection, especially in patients at high bleeding risk.

Reference

Castellucci LA et al. Bleeding Risk with Apixaban vs Rivaroxaban in Acute Venous Thromboembolism. New England Journal of Medicine. 2026;394:1051–1060