Table 1 Drug-specific factors that have been associated with interindividual variability in response to anticoagulation therapy.

From: Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

Drug	Outcome	Factor	Effect	References
Oral anticoagulants
Warfarin	Stable anticoagulation	Age	~8–10% dose reduction per decade	[16, 30]
		Amiodarone	30% dose reduction	[18, 46]
		Smoking	Increased warfarin dose requirement	[22]
		CYP2C92, 3, or 2/3	Decreased warfarin dose requirement; explain 10–15% dose variability	[16, 23, 28,29,30,31]
		CYP2C9*5 rs28371686	Decreased warfarin dose requirement	[23]
		CYP2C9*8 rs7900194	Decreased warfarin dose requirement	[23]
		CYP2C9*11 rs28371685	Decreased warfarin dose requirement	[23]
		rs12777823, near 5′ end of CYP2C18	Decreased warfarin dose requirement	[34]
		FPGS rs7856096	Decreased warfarin dose requirement	[45]
		VKORC1 rs9923231	Increased warfarin dose requirement; explain 20–35% dose variability	[28,29,30,31]
		CYP4F2 rs2108622	Increased warfarin dose requirement; explain 1–7% dose variability	[35, 44, 231]
	Time to therapeutic INR	VKORC1 haplotypes	Decreased time	[40]
	INR ≥ 4	CYP2C92, 3, or 2/3	Increased risk	[27, 31, 232]
	INR ≥ 4	VKORC1 rs9923231	Increased risk	[31, 40]
	Bleeding	CYP2C92, 3, or 2/3	2–3 fold increased risk. CYP2C93/3 versus CYP2C91/1, HR 4.87 (95% CI: 1.38–17.14)	[26, 27]
Dabigatran	Bleeding	CES1 rs2244613	Reduced risk; RR 0.67 (95% CI: 0.55–0.82) per minor allele	[126]
	Major bleeding	P-gp inhibitor (amiodarone 200 mg/day)	25-fold increase in dabigatran trough concentration; major bleeding led to haemorrhagic shock and subsequent death (case report)	[73, 233]
		P-gp inhibitor (dronedarone)	Acute left temporoparietal SDH, with SAH and trace IVH (case report)	[72]
		Concomitant antiplatelet therapy	Dabigatran 110 mg: HR 2.14 (95% CI: 1.75–2.61) Dabigatran 150 mg: HR 2.05 (95% CI: 1.66–2.54)	[83]
		Dual antiplatelets therapy	HR 2.31 (95% CI: 1.79–2.98)	[83]
		Dabigatran 150 mg twice daily (higher rates of bleeding compared to 110 mg twice daily)	Rates of major haemorrhage were 3.74% and 2.99%/year for dabigatran 150 and 110 mg (HR 1.26 (95% CI: 1.04–1.53)	[234]
	Gastrointestinal bleeding	65–74 years of age; ≥75 years of age	HR 2.72 (95% CI: 1.59–4.65); HR 4.52 (95% CI: 2.68–7.64)	[74]
		Male	HR 0.78 (95% CI: 0.64–0.95)	[74]
		Congestive Heart Failure	HR 1.25 (95% CI: 1.01–1.56)	[74]
		Renal impairment	HR 1.67 (95% CI: 1.24–2.25)	[74]
		Alcohol abuse	HR 2.57 (95% CI: 1.52–4.35)	[74]
		Previous Helicobacter pylori infection	HR 4.75 (95% CI: 1.93–11.68)	[74]
		Antiplatelet agent (including prescription aspirin)	HR 1.49 (95% CI: 1.19–1.88)	[74]
		Digoxin	HR 1.33 (95% CI: 1.05–1.68)	[74]
	Stroke	Obesity	Increased GFR and reduced trough plasma level	[92, 93]
	PE	Obesity	Increased risk	[235]
	Trough plasma level	Weight > 100 kg	20% decrease in the trough levels of dabigatran	[87]
		CES1 rs2244613	15% decrease per minor allele; P = 1.2 × 10⁻⁸ (95% CI:10–19)	[126]
	Peak plasma level	CES1 rs8192935	12% decrease per minor allele; P = 3.2 × 10⁻⁸ (95% CI: 8–16)	[126]
	Peak plasma level	ABCB1 rs4148738	12% increase per minor allele; P = 8.2 × 10⁻⁸ (95% CI: 8–17)	[126]
	Bioavailability	P-gp inhibitors	10–20% increase in dabigatran bioavailability	[71]
	Exposure	CrCl 15–30 mL/min	6.3 fold increase	[118]
	Exposure	CrCl 30–50 mL/min	3.2 fold increase	[118]
Rivaroxaban	Clinically relevant bleeding	Aspirin	HR 1.81 (95% CI:1.36–2.41)	[84]
	Clinically relevant bleeding	NSAIDs	HR 1.90 (95% CI:1.45–2.49)	[84]
	Major bleeding	Aspirin	HR 1.50 (95% CI:0.63–3.61)	[84]
	Major bleeding	NSAIDs	HR 2.56 (95% CI:1.21–5.39)	[84]
	Exposure	CrCl <30 mL/min	65% increase	[119]
		CrCl 30–49 mL/min	52% increase	[119]
		CrCl 50–79 mL/min	44% increase	[119]
Apixaban	Major bleeding	Age	HR 1.36 (95% CI:1.23–1.51) per decade increase	[85]
	All-cause mortality	BMI 25–29; BMI > 30 (vs BMI < 25)	HR 0.65 (95%CI: 0.57–0.75); HR 0.61 (95% CI: 0.52–0.71)	[236]
	Composite event rates (stroke/systemic embolism, myocardial infarction and/or all-cause mortality)	BMI 25–29; BMI > 30 (vs BMI < 25)	HR 0.72 (95%CI: 0.64–0.81); HR 0.67 (95% CI: 0.58–0.76)	[236]
	Exposure	CrCl 15–29 mL/min	44% increase	[121]
		CrCl 30–50 mL/min	29% increase	[121]
		CrCl 51–80 mL/min	16% increase	[121]
Edoxaban	Major bleeding	Antiplatelet therapy	Increased incidence of major bleeding compared to patients not receiving antiplatelet therapy; 3.55% per year versus 2.04% per year	[86]
	Major bleeding	Number of dose adjustment factors (CrCl 15–50 mL/min, weight <60 kg, concomitant medication with potent P‐glycoprotein inhibitors) in patients on 30 mg/day	Increased major bleeding in those with 3 vs 0–1 dose adjustment factors. Suggested increased major bleeding with 2 vs 0–1 factors.	[237]
	Exposure	CrCl <30 mL/min	72% increase	[120]
Parenteral anticoagulants
Unfractionated heparin	Markedly low initial aPTT (<1.25x control) in STEMI	Increased weight	RR 1.23 (95% CI 1.15–1.31) per 10 kg increase	[156]
		Younger age	RR 1.42 (95% CI 1.31–1.54) per decade decrease	[156]
		Female	RR 1.55 (95% CI 1.24–1.95)	[156]
	Markedly high initial aPTT (≥2.75x control) in STEMI	Increased age	RR 1.14 (95% CI 1.06–1.23) per decade increase	[156]
		Female	RR 1.46 (95% CI 1.21–1.78)	[156]
		Lower weight	RR 1.19 (95% CI 1.11–1.27)	[156]
		Renal dysfunction	RR 1.08 (95% CI 1.02–1.13) per 0.2 mg/dL increase in serum creatinine	[156]
	180 day VTE recurrence after incident VTE	Attainment of aPTT ≥58 s within 24 ± 4 h of starting UFHⁱ	HR 0.57 (95% CI 0.34–0.97)	[155]
	180 day VTE recurrence after incident VTE	Proportion of time with aPTT ≥40 s per 10% increase	HR 0.90 (95% CI 0.83–0.97)	[155]
	MI recurrence following STEMI	Markedly low aPTTs (<1.25x control) taken 4–6 h after starting UFH therapyⁱ	OR 3.0 (95% CI 1.28–7.04)	[156]
	Heparin resistance	Antithrombin deficiency, Platelet count >300,000/microL, Recent heparin therapy, Increased levels of heparin-binding proteins, increased heparin clearance, high levels of factor VIII and fibrinogen, concomitant use of aprotinin	Increased risk of heparin resistance	[144, 160, 162, 163]
	Bleeding	Markedly high initial aPTT (≥2.75x control) in STEMIⁱ	OR 1.72 (95% CI 0.98–3.00)	[156]
	Heparin-induced thrombocytopaenia	UFH compared to LMWH in surgical patients	OR 0.10 (95% CI 0.01–0.2)	[171]
		Therapeutic UFH	IV therapeutic UFH: 0.76% develop HIT SC prophylactic UFH: <0.1% develop HIT	[173]
		Female	OR 2.37 (95 CI 1.37–4.09)	[174]
		TDAG8 rs10782473	OR 18.52 (95% CI 6.33–54.23)	[178]
		HLA-DRA rs4348358	OR 0.25 (95% CI 0.15–0.44)	[178]
		PTPRJ rs1566734 (Q267P)	OR 0.36 (95% CI 0.20–0.67)	[176]
		PTPRJ rs1503185 (R326Q)	OR 0.37 (95% CI 0.20–0.68)	[176]
	Thrombosis in HIT	FCGR2A rs1801274 (H131R)	OR 5.9 (95% CI 1.7–20)	[177]
	Hyperkalaemia	Longer hospitalisation duration	Increased risk (p < 0.05)	[185]
		Baseline serum potassium	OR 43.1 (95% CI 1.40–45.76)	[181, 185]
		Diabetes mellitus	Increased risk (p < 0.001)	[185]
		Metabolic acidosis	Increased risk (p < 0.005)	[185]
		Renal dysfunction	Increased risk	[182, 238]
	Osteoporosis	Long term UFH therapy in pregnant patients	Bone mineral density reduction (≤30% patients) Osteoporotic fractures (2.2–5% patients)	[239, 240]
Low molecular weight heparins	Low anti-Xa activity	Weight	A negative correlation between body weight and anti-Xa activity (Spearman’s rho = −0.428)	[191]
		Peripheral oedema	Anti-Xa AUC_0–12 h if oedematous: 0.63 IU/L Anti-Xa AUC_0–12 h if non-oedematous: 1.57 IU/L (p = 0.001)	[205]
		Multiple organ dysfunction	OR 1.56 (95% CI 1.15–2.12)	[206]
		COVID-19	Decreased recovery of anti-Xa of the COVID19 patients assessed, p < 0.05 (t test), with the maximum recovery being 82% and the minimum recovery being 58% when compared with a calculated expected recovery.	[241]
	High anti-Xa activity	Weight ≤45 kg vs 51–55 kg	OR 5.52 (95% CI 0.91–33.57)	[191]
		Renal dysfunction	Enoxpararin Thromboprophylaxis: significant accumulation Therapeutic: significant accumulation	[193]
			Nadroparin Thromboprophylaxis: no accumulation Therapeutic: significant accumulation	[223, 224]
			Dalteparin Thromboprophylaxis: no accumulation Therapeutic: no accumulation	[193, 227]
			Tinzaparin Thromboprophylaxis: no accumulation Therapeutic: no accumulation	[225, 226]
		Body weight ≤45 kg vs 51–55 kg	OR 5.52 (95% CI 0.91–33.57)	[191]
	DVT in high risk surgical and trauma patients	Low trough anti-Xa (≤0.1 IU/mL) activityⁱⁱⁱ	Increased DVT risk (p = 0.026)	[207]
	Bleeding	Therapeutic enoxaparin with CrCl ≤ 30 mL	OR 3.88 (95% CI 1.78–8.45)	[230]
	Bleeding	anti-Xa activity >0.9 IU/mLⁱⁱ	OR 1.6 (95% CI 1.0–2.5) per unit of anti-Xa	[201]

i = the associations between aPTT on heparin and thrombotic or haemorrhagic endpoints are inconsistent and have not been observed in other studies; ii = the associations between anti-Xa on low molecular weight heparin and thrombotic or haemorrhagic endpoints are inconsistent and have not been observed in other studies.
ABCB1 ATP-binding cassette sub-family B member 1, aPTT activated partial thromboplastin time, AUC area under the curve, BMI body mass index, CES1 carboxylesterase 1, CI confidence interval, CrCl creatinine clearance, CYP cytochrome P450, DVT Deep vein thrombosis, FCGR2A Fc fragment of IgG, low affinity IIa, receptor, FPGS folylpolyglutamate synthase, GFR glomerular filtration rate, HIT heparin-induced thrombocytopaenia, HLA-DRA human leucocyte antigen class II, DR alpha, HR hazard ratio, INR international normalised ratio, IU International units, IVH intraventricular haemorrhage, IV Intravenous, LMWH low molecular weight heparin, MI myocardial infarction OR odds ratio, PE pulmonary embolism, P-gp permeability glycoprotein, PTPRJ protein tyrosine phosphatase receptor type J (CD148), RR relative risk, SAH subarachnoid haemorrhage, SC subcutaneous, SDH subdural haematoma; STEMI ST segment elevation myocardial infarction; TDAG8 T-cell death-associated gene 8, UFH unfractionated heparin, VKORC1 vitamin K 2,3 epoxide reductase complex 1, VTE venous thromboembolism.

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Table 1 Drug-specific factors that have been associated with interindividual variability in response to anticoagulation therapy.

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