Pharmacogenetics to Avoid Adverse Reactions in Cardiology: Ready for Implementation?
Abstract
:1. Introduction
2. Cardiovascular Drugs in Pharmacogenetics Guidelines
2.1. Anticoagulants
Warfarin
- Warfarin and CYP2C9
- Warfarin and VKORC1
- Warfarin and CYP4F2
- Acenocoumarol/phenprocoumon and VKORC1
2.2. Antiplatelets
- Clopidogrel and CYP2C19
2.3. Statins
- Simvastatin and SLCO1B1
- Atorvastatin and SLCO1B1
2.4. Beta-Blockers
- Metoprolol and CYP2D6
2.5. Antiarrithmics
- Flecainide and CYP2D6
- Propafenone and CYP2D6
2.6. Other Drugs Used in Cardiology
3. Differences in Therapeutic Recommendations
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Reviewed with Recommendation | Reviewed with No Recommendation |
---|---|
Acenocoumarol-VKORC1 (DPWG [13], RNPGx [14]) Atorvastatin-SLCOB1 (DPWG [15]) Clopidogrel-CYP2C19 (CPIC [16], DPWG [17], RNPGx [14]) Flecainide-CYP2D6 (DPWG [18]) Metoprolol-CYP2D6 (DPWG [19]) Phenprocoumon-VKORC1 (DPWG [20]) Propafenone-CYP2D6 (DPWG [21]) Simvastatin-SLCOB1 (CPIC [22], DPWG [23], RNPGx [14]) Warfarin-CYP2C9 (CPIC [24], DPWG [25], CPNDS [26], RNPGx [14]) Warfarin-VKORC1 (CPIC [24], DPWG [27], RNPGx [14]) Warfarin-CYP4F2 (CPIC [24]) | Acenocoumarol-CYP2C9 (DPWG [28]) Amiodarone-CYP2D6 (DPWG [29]) Aspirin-CYP2C9 (CPIC [30]) Atenolol-CYP2D6 (DPWG [31]) Bisoprolol-CYP2D6 (DPWG [32]) Carvedilol-CYP2D6 (DPWG [33]) Clonidine-CYP2D6 (DPWG [34]) Disopyramide-CYP2D6 (DPWG [35]) Fluvastatin-SLCOB1 (DPWG [36]) Phenprocoumon-CYP2C9 (DPWG [37]) Prasugrel-CYP2C19 (DPWG [38]) Quinidine-CYP2D6 (DPWG [39]) Sotalol-CYP2D6 (DPWG [40]) Ticagrelor-CYP2C19 (DPWG [41]) |
Drug | Gene | Guideline | Genotype/Phenotype | Therapeutic Recommendation | Level of Evidence |
---|---|---|---|---|---|
Warfarin | CYP2C9 Combined with VKORC1 and CYP4F2 | CPIC 2017 | *1/*2 | Use validated pharmacogenetics algorithms to calculate initial dose | Strong (Non-African) Moderate (African) |
*1/*3 | |||||
*2/*2 | |||||
*2/*3 | |||||
*3/*3 | |||||
Warfarin | CYP2C9 | DPWG 2018 | *1/*2 (IM) | Use initial standard dose | 4A |
*1/*3 (IM) | Use 65% of the standard initial dose. Specific dose can be calculated using an algorithm | 4D | |||
*2/*2 (PM) | Use 65% of the standard initial dose. Specific dose can be calculated using an algorithm | 4A | |||
*2/*3 (PM) | Use 45% of the standard initial dose. Specific dose can be calculated using an algorithm | 4A | |||
*3/*3 (PM) | Use 20% of the standard initial dose. Specific dose can be calculated using an algorithm | 4C | |||
Warfarin | CYP2C9 Combined with VKORC1 | RNPGx 2017 | *1/*1 | Suggested initial dose between 5 and 7 mg or 3 and 4 mg depending on VKORC1 genotype | A priori genotyping: advisable A posteriori: advisable |
*1/*2 (IM) | Suggested initial dose between 5 and 7 mg or 3 and 4 mg depending on VKORC1 genotype | ||||
*1/*3 (IM) | Suggested initial dose between 3 and 4 mg or 0.5 and 2 mg depending on VKORC1 genotype | ||||
*2/*2 (PM) | Suggested initial dose between 3 and 4 mg or 0.5 and 2 mg depending on VKORC1 genotype | ||||
*2/*3 (PM) | Suggested initial dose between 3 and 4 mg or 0.5 and 2 mg depending on VKORC1 genotype | ||||
*3/*3 (PM) | Suggested initial dose between 0.5 and 2 mg | ||||
Warfarin | CYP2C9 Combined with VKORC1 | CPNDS 2015 | *2 | Use pharmacogenetic dosing algorithm to estimate the required dose | Strong A |
*3 | |||||
Warfarin | VKORC1 Combined with CYP2C9 and CYP4F2 | CPIC 2017 | −1639 AG | Use validated pharmacogenetics algorithms to calculate initial dose | Strong (Non-African) Moderate (African) |
−1639 GG | |||||
Warfarin | VKORC1 | DPWG 2018 | −1639 AG | Use initial standard dose | 4A |
−1639 GG | Use 60% of the standard initial dose. Specific dose can be calculated using an algorithm | 4A | |||
Warfarin | VKORC1 Combined with CYP2C9 | RNPGx 2017 | −1639 GG | Suggested initial dose between 5 and 7, 3 and4 or 0.5 and 2 mg depending on VKORC1 genotype | 1A |
−1639 AG | Suggested initial dose between 5 and7, 3and 4 or 0.5 and 2 mg depending on VKORC1 genotype | ||||
−1639 AA | Suggested initial dose between 5–7, 3–4 or 0.5–2 mg depending on VKORC1 genotype | ||||
Warfarin | VKORC1 Combined with CYP2C9 | CPNDS 2015 | −1639 AG | Use pharmacogenetic dosing algorithm to estimate the required dose | Strong A |
−1639 GG | |||||
Warfarin | CYP4F2 Combined with CYP2C9 and VKORC1 | CPIC 2017 | rs2108622 T | Increase initial dose calculated with algorithm by 5–10% | Optional |
Acenocoumarol | VKORC1 | DPWG 2018 | −1639 AG | Use initial standard dose | 4C |
−1639 AA | Use 50% of the standard initial dose. Recommend more frequent INR monitoring | 4F | |||
Phenprocoumon | VKORC1 | DPWG 2018 | −1639 AG | Use initial standard dose | 4D |
−1639 AA | Use 50% of the standard initial dose. Recommend more frequent INR monitoring | 4D |
Drug | Gene | Guideline | Genotype/Phenotype | Therapeutic Recommendation | Level of Evidence |
---|---|---|---|---|---|
Clopidogrel | CYP2C19 | CPIC 2013 | UM (*1/*17 or *17/*17) | Label recommended dosage and administration | Strong |
EM (*1/*1) | Label recommended dosage and administration | Strong | |||
IM (*1/*2; *1/*3 or *2/*17) | Alternative antiplatelet therapy (if no contraindication) | Moderate | |||
PM (*2/*2; *2/*3 or *3/*3) | Alternative antiplatelet therapy (if no contraindication) | Strong | |||
Clopidogrel | CYP2C19 | DPWG 2018 | UM (*17/*17) | Label recommended dosage and administration | 4A |
IM (*1/*2; *1/*3; *2/*17 or *3/*17) | Percutaneous coronary intervention, stroke or TIA: choose an alternative or double the dose to 150 mg/day (600 mg loading dose). Other indications: no action required | 4F | |||
PM (*2/*2; *2/*3 or *3/*3) | Percutaneous coronary intervention, stroke or TIA: choose an alternative or double the dose to 150 mg/day (600 mg loading dose). Other indications: determine the level of inhibition of platelet aggregation by clopidogrel. Consider an alternative in poor responders | 4F | |||
Clopidogrel | CYP2C19 | RNPGx 2017 | UM (*1/17 or *17/*17) | Label recommended dosage and administration | A priori genotyping: Coronary angioplasty: essential Other: potentially useful A posteriori: advisable |
EM (*1/*1) | Label recommended dosage and administration | ||||
IM (*1/*2 or *1/*3) | Alternative antiplatelet therapy | ||||
PM (*2/*2; *3/*3) | Alternative antiplatelet therapy |
Drug | Gene | Guideline | Genotype/Phenotype | Therapeutic Recommendation | Level of Evidence |
---|---|---|---|---|---|
Simvastatin | SLCO1B1 | CPIC 2014 | IM (CT) | Lower dose or consider an alternative statin (consider routine CK surveillance) | Strong |
PM (CC) | Lower dose or consider an alternative statin (consider routine CK surveillance) | Strong | |||
Simvastatin | SLCO1B1 | DPWG 2020 | 521 CT | 1. Choose an alternative 2. If not possible: (a) Avoid simvastatin doses exceeding 40mg/day. (b) Advise the patient to contact their doctor in the event of muscle symptoms. | 4D |
521 CC | Choose an alternative drug | 4D | |||
Simvastatin | SLCO1B1 | RNPGx 2017 | 521 TT | Avoid maximum dose (80 mg) during the first year of treatment | A priori genotyping: no indication A posteriori: potentially useful |
521 CT | Reduce the dose to max. 20 mg per day. Close CPK monitoring and avoid OATP1B1 inhibitors | ||||
521 CC | Reduce the dose to max. 20 mg per day. Close CPK monitoring and avoid OATP1B1 inhibitors | ||||
Atorvastatin | SLCO1B1 | DPWG 2020 | 521 CT | Additional risk factors for myopathy: 1. Choose an alternative 2. If not possible: Advise the patient to contact their doctor in the event of muscle symptoms. No additional risk factors for myopathy: Advise the patient to contact their doctor in the event of muscle symptoms. | 4C |
521 CC | Additional risk factors for myopathy: 1. Choose an alternative 2. If not possible: Advise the patient to contact their doctor in the event of muscle symptoms. No additional risk factors for myopathy: Advise the patient to contact their doctor in the event of muscle symptoms. | 4C |
Drug | Gene | Guideline | Genotype/Phenotype | Therapeutic Recommendation | Level of Evidence |
---|---|---|---|---|---|
Metoprolol | CYP2D6 | DPWG 2018 | UM | 1. Use the maximum dose for the relevant indication as a target dose. 2. If effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative. | 4D |
IM | Gradual reduction of heart rate or in the event of symptomatic bradycardia: 1. increase the dose in smaller steps and/or prescribe no more than 50% of the standard dose. Other cases: no action required. | 4A | |||
PM | Gradual reduction of heart rate or in the event of symptomatic bradycardia: 1. increase the dose in smaller steps and/or prescribe no more than 25% of the standard dose. Other cases: no action required. | 4C |
Drug | Gene | Guideline | Genotype/Phenotype | Therapeutic Recommendation | Level of Evidence |
---|---|---|---|---|---|
Flecainide | CYP2D6 | DPWG 2018 | UM | Monitor the plasma concentration as a precaution and record an ECG or select an alternative | NA |
IM | Indications other than diagnosis of Brugada syndrome: reduce the dose to 75% of the standard dose and record an ECG and monitor the plasma concentration. Provocation test for diagnosis of Brugada syndrome: No action required. | 3A | |||
PM | Reduce the dose to 50% of the standard dose and record an ECG and monitor the plasma concentration. | 4F | |||
Propafenone | CYP2D6 | DPWG 2018 | UM | Monitor the plasma concentration as a precaution and record an ECG or select an alternative (possible reduced efficacy) | 3D |
IM | Monitor the plasma concentration as a precaution and record an ECG or select an alternative (be alert to side effects) | 3A | |||
PM | Reduce the dose to 30% of the standard dose, perform an ECG and monitor plasma concentrations. | 4C |
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García-González, X.; Salvador-Martín, S. Pharmacogenetics to Avoid Adverse Reactions in Cardiology: Ready for Implementation? J. Pers. Med. 2021, 11, 1180. https://doi.org/10.3390/jpm11111180
García-González X, Salvador-Martín S. Pharmacogenetics to Avoid Adverse Reactions in Cardiology: Ready for Implementation? Journal of Personalized Medicine. 2021; 11(11):1180. https://doi.org/10.3390/jpm11111180
Chicago/Turabian StyleGarcía-González, Xandra, and Sara Salvador-Martín. 2021. "Pharmacogenetics to Avoid Adverse Reactions in Cardiology: Ready for Implementation?" Journal of Personalized Medicine 11, no. 11: 1180. https://doi.org/10.3390/jpm11111180