Nattokinase and Serrapeptase Combination: Evidence-Based Assessment
Direct Answer
The combination of nattokinase and serrapeptase lacks high-quality evidence supporting cardiovascular benefits, and neither agent has established efficacy for preventing or treating cardiovascular disease based on rigorous clinical trials.
Evidence Quality and Clinical Utility
Nattokinase
The most recent and highest-quality study demonstrates nattokinase has no effect on cardiovascular outcomes. A 2021 randomized controlled trial of 265 individuals followed for 3 years showed nattokinase supplementation (2,000 fibrinolytic units daily) had no significant effect on subclinical atherosclerosis progression measured by carotid intima-media thickness, carotid arterial stiffness, or blood pressure 1.
Pharmacokinetic Data
- Peak serum levels occur approximately 13.3 hours after oral ingestion of a single 2,000 FU dose 2
- Nattokinase is detectable in human blood following oral administration, confirming bioavailability 2
Laboratory Effects Without Clinical Benefit
- A 2009 study showed nattokinase decreased fibrinogen by 7-10%, factor VII by 7-14%, and factor VIII by 17-19% after 2 months 3
- However, these laboratory changes did not translate to clinical cardiovascular benefit in the definitive 2021 trial 1
Safety Profile
- A 2021 observational study in 153 vascular surgery patients reported no adverse drug reactions when nattokinase (100 mg/day) was combined with anticoagulants 4
- Critical caveat: This was not a controlled trial and involved close INR monitoring, which would not occur in typical supplement use 4
Serrapeptase
The evidence for serrapeptase is even weaker than nattokinase, with no credible cardiovascular benefit demonstrated. A 2013 systematic review concluded that "the existing scientific evidence for Serratiopeptidase is insufficient to support its use as an analgesic and health supplement" 5.
Evidence Quality Issues
- Studies supporting serrapeptase are of poor methodology with small sample sizes 5
- Doses and treatment duration often unspecified 5
- No randomized controlled trials demonstrate cardiovascular benefit 5
- Long-term safety data is lacking 5
Dosing Information (If Used Despite Lack of Evidence)
Nattokinase
- Studied dose: 2,000 fibrinolytic units (FU) daily, typically as a single dose 2, 1
- Equivalent to approximately 100 mg of nattokinase extract 2
- Administered orally, usually in capsule form 2, 4
Serrapeptase
- No standardized cardiovascular dose exists due to lack of quality trials 5
- Doses in published studies vary widely and are poorly documented 5
Combination Therapy
- No published studies exist examining nattokinase and serrapeptase combination therapy
- No evidence supports synergistic benefit
- Potential for additive bleeding risk when combined with anticoagulants or antiplatelet agents
Critical Clinical Considerations
Bleeding Risk
- Both agents have theoretical fibrinolytic and proteolytic activity 2, 5
- Patients on anticoagulants (warfarin, DOACs) or antiplatelet therapy (aspirin, clopidogrel) face increased bleeding risk 4
- Unlike pharmaceutical anticoagulants, these supplements lack standardized monitoring protocols 5
Lack of Guideline Support
- No major cardiovascular society (ESC, AHA/ACC, ADA) recommends nattokinase or serrapeptase for cardiovascular disease prevention or treatment 6
- Established therapies (statins, aspirin, ACE inhibitors, ARBs) have robust mortality and morbidity benefits 6
Opportunity Cost
- Patients using these supplements instead of proven therapies miss established cardiovascular risk reduction 6
- Statins reduce major adverse cardiovascular events by 30-40% in appropriate populations 6
- Aspirin reduces myocardial infarction by 30% and stroke by 20% in high-risk patients 6
Evidence-Based Recommendation
For cardiovascular health, prioritize guideline-recommended therapies with proven mortality and morbidity benefits:
- Statin therapy for LDL cholesterol reduction in patients ≥40 years with diabetes or cardiovascular risk factors 6
- Aspirin 75-162 mg daily for secondary prevention or primary prevention in high-risk patients 6
- ACE inhibitors or ARBs for patients with hypertension, diabetes, or heart failure 6, 7, 8
- Lifestyle modifications including diet, exercise, and smoking cessation 6
If patients insist on nattokinase despite lack of evidence: 2,000 FU daily with close monitoring for bleeding, particularly if on anticoagulants 4, 1. Serrapeptase cannot be recommended given insufficient evidence 5.