Note: This is a multi-article spread containing a shared commentary. Please scroll down for the other article(s).
Therapeutics
Warfarin dosing by genotype did not improve time in therapeutic range
Kimmel SE, French B, Kasner SE, et al; the COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013;369:2283-93.
Clinical impact ratings: F ★★★★★✩✩ C ★★★★★★✩ H ★★★★★★✩ Question In patients initiating warfarin therapy, what are the effects of dosing based on genotype and clinical factors compared with clinical factors alone?
Methods Design: Randomized controlled trial (Clarification of Optimal Anticoagulation through Genetics [COAG] trial). ClinicalTrials.gov NCT00839657. Allocation: {Concealed}*.† Blinding: Blinded† (patients, clinicians, {data collectors}* and adverse event adjudicators). Follow-up period: 28 days. Setting: 18 centers in the USA. Patients: 1015 inpatients or outpatients ≥ 18 years of age (median age 57 to 59 y, 51% men) who were initiating warfarin therapy for ≥ 1 month with a target international normalized ratio (INR) of 2 to 3. Initial warfarin dosing based on genotype and clinical factors vs clinical factors alone‡ Outcomes at 28 d
Genotype and Clinical clinical factors factors
% time in therapeutic range
45.2%
45.4%
Event rates Composite secondary outcome§ Any INR ≥ 4 Major bleeding
−0.2% (−3.4 to 3.1)
RRR/RRI (CI)
20%
21%
RRI 0.9% (−21 to 28)
19%
18%
RRI 7% (−17 to 38)
0.8%
Thromboembolism
Mean difference (95% CI)
2.0%
RRR 59% (−31 to 87)
1.0%
0.8%
RRI 27% (−66 to 366)
Nonmajor bleeding
2.5%
4.0%
RRR 38% (−26 to 70)
Mortality
0.4%
0.2%
RRI 109% (−81 to 2171)
‡INR = international normalized ratio; other abbreviations defined in Glossary. RRR, RRI, and CI calculated from control event rates and hazard ratios in article. Results were adjusted for study center and race.
Intervention: Warfarin dosing based on genotype for CYP2C9*2, CYP2C9*3, and VKORC1 and clinical factors (n = 514) or clinical factors alone (n = 501) during the first 5 days of therapy, using a dose-initiation algorithm on days 1 to 3 and a dose-revision algorithm on days 4, 5, or both. Standardized INR-based doseadjustment methods were used after day 5. Outcomes: Primary outcome was percentage of time in therapeutic range (TTR) (INR 2 to 3) from day 4 or 5 to day 28, calculated using the Rosendaal method of standard linear interpolation between successive INR values. Secondary outcomes included a composite of any INR ≥ 4, major bleeding, or thromboembolism; clinically relevant nonmajor bleeding; and mortality. 1022 patients were required to detect a 5.5% difference in TTR (80% power, α = 0.04). Patient follow-up: 94% (modified intention-to-treat analysis for patients with INR data).
Main results Groups did not differ for TTR, any INR ≥ 4, major bleeding, thromboembolism, clinically relevant nonmajor bleeding, or mortality (Table).
Conclusion In patients initiating warfarin therapy, dosing based on genotype and clinical factors or clinical factors alone did not differ for time in therapeutic range at 28 days. *Information provided by author.. †See Glossary.
Sources of funding: National Heart, Lung, and Blood Institute. BristolMyers Squibb provided the warfarin, and GenMark Diagnostics and AutoGenomics lent the genotyping platforms. For correspondence: Dr. S.E. Kimmel, Center for Therapeutic Effectiveness Research, Philadelphia, PA, USA. E-mail stevek@mail. med.upenn.edu. ■
§Composite of any INR ≥ 4, major bleeding, or thromboembolism.
Commentary Pharmacogenetics holds the potential for a personalized approach to clinical management due to the increasing ability to determine genotypes that contribute to medication metabolism and effectiveness. Vitamin K antagonist (VKA) dosing has been a model for the field as 2 of the major genetic determinants of VKA effectiveness are well-described: Sensitivity to VKAs is affected by polymorphisms of the cytochrome P-450 system (CYP2C9) responsible for VKA metabolism and for the gene encoding vitamin K epoxide reductase, which is necessary for the production of activated clotting factors II, VII, IX, and X (1). Thus, knowledge of a patient’s genotype could potentially help guide dosing and prevent adverse events. Previous studies have been limited by small size (2, 3) or observational design (4) and have had mixed results. JC8
© 2014 American College of Physicians
These 3 large, rigorous, randomized trials assessed genotypeguided VKA dosing and have increased our understanding of the utility of these tests. 2 trials found no benefit, and the third found a modest increase in the percentage of TTR but no change in clinical outcomes. Examining differences between the trials can help to assess whether there are any patient groups for whom this strategy may be useful. Verhoef and colleagues assessed acenocoumarol and phenprocoumon rather than warfarin, which may explain the lack of benefit since the CYP2C9 enzyme affects phenprocoumon metabolism less than warfarin (5). The trial by Kimmel and colleagues examined warfarin dosing and enrolled an ethnically diverse population, and over half of patients had VTE. A prespecified subgroup analysis found that genotype-based dosing increased risk for INRs above the therapeutic range more than (continued on page 9) 18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929862/ by a Imperial College London User on 07/24/2017
Therapeutics
In AF or VTE, warfarin dosing by genotype improved time in therapeutic range but not clinical outcomes
Pirmohamed M, Burnside G, Eriksson N, et al; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369:2294-303.
Clinical impact ratings: F ★★★★★✩✩ C ★★★★★✩✩ H ★★★★★★✩ Question In patients initiating warfarin therapy for atrial fibrillation (AF) or venous thromboembolism (VTE), does genotype-guided dosing improve anticoagulation control compared with standard dosing?
Methods Design: Randomized controlled trial (European Pharmacogenetics of Anticoagulant Therapy [EU-PACT] warfarin trial). ClinicalTrials.gov NCT01119300. Allocation: Concealed.*
Intervention: Warfarin dosing based on clinical factors and genotype for CYP2C9*2, CYP2C9*3, and VKORC1 (determined with a point-of-care test) for the first 5 days, using a loading-dose algorithm on days 1 to 3 and a dose-revision algorithm on days 4 and 5 (n = 227) or standard warfarin dosing, with a 3-day loadingdose regimen (≤ 75 y: 10 mg on day 1 and 5 mg/d on days 2 and 3; > 75 y: 5 mg/d on days 1 to 3) and dosing according to usual local clinical practice on days 4 and 5 (n = 228). After day 5, all patients were managed according to local clinical practice. Outcomes: Primary outcome was percentage of time in therapeutic range (TTR) (INR 2 to 3), calculated using the Rosendaal method. Secondary outcomes included any INR ≥ 4, major and minor bleeding events, and thromboembolism.
Blinding: Blinded* (patients). Follow-up period: 3 months. Setting: 3 centers in the UK and 2 centers in Sweden.
Patient follow-up: 94% (with INR data for ≥ 13 d).
Patients: 455 warfarin-naïve patients ≥ 18 years of age (mean age 67 y, 61% men, 72% with AF) who had AF or VTE, were starting anticoagulation with warfarin, and had a target international normalized ratio (INR) of 2 to 3. Initial warfarin dosing based on genotype vs standard dosing in atrial fibrillation or venous thromboembolism† Outcomes at 3 mo
Genotype
Standard Mean difference (95% CI)
% time in therapeutic range
67%
INR ≥ 4.0
27%
37%
Bleeding events
37%
38%
60%
Event rates
7% (3 to 11)
RRR (CI) 27% (2 to 48) 3% (−26 to 28)
NNT (CI) 11 (6 to 143) Not significant
†INR = international normalized ratio; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from control event rates and odds ratios in article. Mean difference was adjusted for study center and indication.
Commentary (continued from page 8) dosing based on clinical factors for black patients, possibly due to variant alleles being less common in black than white patients (6). The effect of the indication for warfarin on the performance of genotype-guided dosing is unknown, although VTE patients are more acutely ill and more likely to start parenteral heparin concurrently than AF patients. The trial by Pirmohamed and colleagues found a modest benefit for genotype-based dosing in time to reach therapeutic range and TTR. This study used warfarin and enrolled 98% white patients, 72% of whom had AF, and compared an algorithm combining genetic and clinical factors with a strategy based on a loading-dose regimen followed by usual practice. Although not specifically powered to assess clinical outcomes, none of the trials found any difference in clinical endpoints, including bleeding. Overall, the 3 trials indicate that genotype-guided dosing may add marginal benefit in the surrogate outcome of obtaining a therapeutic INR for white patients starting warfarin but is unlikely to have any meaningful effect on clinical outcomes. This adds to 18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Main results The main results are in the Table. There were no major bleeding events and 1 thromboembolic event in the standard care group.
Conclusion In patients who are initiating warfarin therapy for atrial fibrillation or venous thromboembolism, genotype-guided dosing improved time in therapeutic range at 3 months, but not bleeding events, compared with standard dosing. *See Glossary.
Source of funding: European Commission Seventh Framework Programme. For correspondence: Dr. M. Pirmohamed, University of Liverpool, Liverpool, England, UK. E-mail [email protected]. ■
previous evidence and recommendations not to use pharmacogenetic testing for warfarin (7). It is uncertain why genotype-guided dosing fails to improve warfarin management, although it probably relates to the availability of the INR value to guide dosing. Pharmacogenetic-based dosing may prove to be more beneficial for medications that have no laboratory or clinical marker to guide dosing or gauge effectiveness. The feasibility of obtaining genotype results in a timely manner may also play a role, as only 45% of patients in the trial by Kimmel and colleagues had results available before the first warfarin dose. However, this information was available before the second dose for 94% of patients. The cost for these 2 assays will vary but generally ranges from $200 to $575 (8). Given the cost and lack of proven clinical benefit, clinicians should forgo genotype testing and concentrate on optimizing processes of care that make warfarin management challenging. These trials confirm the difficulties clinicians face in managing warfarin; despite the study settings, the percentage of TTR was only 45% to 67%, and the median time to reach a therapeutic INR was 21 to 29 days. High-quality warfarin management (continued on page 10) © 2014 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929862/ by a Imperial College London User on 07/24/2017
JC9
Therapeutics
In AF or VTE, acenocoumarol or phenprocoumon dosing by genotype did not affect time in therapeutic range
Verhoef TI, Ragia G, de Boer A, et al; EU-PACT Group. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med. 2013;369:2304-12.
Clinical impact ratings: C ★★★★★✩✩ H ★★★★★★✩ Question In patients who are initiating acenocoumarol or phenprocoumon therapy for atrial fibrillation (AF) or venous thromboembolism (VTE), what are the effects of dosing based on genotype and clinical factors compared with clinical factors alone?
Methods Design: 2 randomized controlled trials (European Pharmacogenetics of Anticoagulant Therapy [EU-PACT] acenocoumarol trial and EU-PACT phenprocoumon trial). ClinicalTrials.gov NCT01119261 and NCT01119274. The trials were combined due to low enrollment. Allocation: {Concealed}*.† Blinding: Blinded† (patients and {data safety and monitoring committee}*). Follow-up period: 12 weeks. Setting: 4 centers in the Netherlands (acenocoumarol and phenprocoumon) and 3 centers in Greece (acenocoumarol). Patients: 548 coumarin-naïve patients ≥ 18 years of age (mean age 68 y, 59% men, 83% with AF) who had AF or VTE and were
starting acenocoumarol (n = 381) or phenprocoumon (n = 167) treatment for ≥ 12 weeks with target international normalized ratio (INR) of 2 to 3. Intervention: Acenocoumarol or phenprocoumon dosing based on genotypes for VKORC1 and CYP2C9 (determined with a point-of-care test) and clinical factors (n = 273) or clinical factors alone (n = 275) for the first 5 to 7 days. Thereafter, dosing was based on INR and local clinical practice. Therapy was initiated as outpatient care in the Netherlands and inpatient care in Greece. Outcomes: Primary outcome was percentage of time in therapeutic range (TTR) (INR 2 to 3), calculated using the Rosendaal method. Secondary outcomes included any INR ≥ 4, major and minor bleeding, and thromboembolism. 200 patients were needed per group to detect a 7% improvement in TTR, with a standard deviation of 23% and a 10% withdrawal rate (80% power, α = 0.05). Patient follow-up: 88% (modified intention-to-treat analysis of patients with ≥ 10 wk follow-up).
Main results The main results are in the Table.
Conclusion Initial acenocoumarol or phenprocoumon dosing based on genotype and clinical factors vs clinical factors alone in atrial fibrillation or venous thromboembolism‡ Outcomes at 12 wk
Genotype and Clinical factors Mean difference clinical factors (95% CI)
% time in therapeutic range
61.6%
INR ≥ 4.0
31%
60.2%
1.4% (−2.8 to 5.5)
33%
6% (−21 to 28)
Event rates
RRR (CI)
Events/person mo
P value
Bleeding events
0.38
0.38
0.94
Thromboembolic events
0.02
0.01
0.62
‡INR = international normalized ratio; other abbreviations defined in Glossary. RRR and CI calculated from event rates in article.
In patients initiating acenocoumarol or phenprocoumon therapy for atrial fibrillation or venous thromboembolism, dosing based on genotype and clinical factors or clinical factors alone did not differ for time in therapeutic range at 12 weeks. *Information provided by author. †See Glossary.
Sources of funding: European Commission Seventh Framework Programme; Swedish Research Council; Swedish Heart-Lung Foundation. LGC provided point-of-care assays. For correspondence: Dr. A.H. Maitland-van der Zee, Utrecht University, Utrecht, The Netherlands. E-mail [email protected]. ■
Commentary (continued from page 9) may include access to a structured anticoagulation clinic, providing appropriate patient education, ensuring frequent INR testing during initiation, real-time dose adjustment in the outpatient setting, using evidence-based approaches to manage periprocedural anticoagulation, and optimizing communication among providers during transitions of care. Andrew Dunn, MD, MPH, SFHM, FACP Mount Sinai Health System New York, New York, USA
JC10
© 2014 American College of Physicians
References 1. Voora D, McLeod HL, Eby C, Gage BF. Pharmacogenomics. 2005;6:503-13. 2. Anderson JL, Horne BD, Stevens SM, et al; Couma-Gen Investigators. Circulation. 2007;116:2563-70. 3. Burmester JK, Berg RL, Yale SH, et al. Genet Med. 2011;13:509-18. 4. Gong IY, Tirona RG, Schwarz UI, et al. Blood. 2011;118:3163-71. 5. Kirchheiner J, Ufer M, Walter EC, et al. Pharmacogenetics. 2004;14:19-26. 6. Takahashi H, Wilkinson GR, Nutescu EA, et al. Pharmacogenet Genomics. 2006;16:101-10. 7. Holbrook A, Schulman S, Witt DM, et al; American College of Chest Physicians. Chest. 2012;141:e152S-84S. 8. Patrick AR, Avorn J, Choudry NK. Circ Cardiovasc Qual Outcomes. 2009;2:429-36
18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929862/ by a Imperial College London User on 07/24/2017
Therapeutics
Warfarin dosing by genotype did not improve time in therapeutic range
Kimmel SE, French B, Kasner SE, et al; the COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013;369:2283-93.
Clinical impact ratings: F ★★★★★✩✩ C ★★★★★★✩ H ★★★★★★✩ Question In patients initiating warfarin therapy, what are the effects of dosing based on genotype and clinical factors compared with clinical factors alone?
Methods Design: Randomized controlled trial (Clarification of Optimal Anticoagulation through Genetics [COAG] trial). ClinicalTrials.gov NCT00839657. Allocation: {Concealed}*.† Blinding: Blinded† (patients, clinicians, {data collectors}* and adverse event adjudicators). Follow-up period: 28 days. Setting: 18 centers in the USA. Patients: 1015 inpatients or outpatients ≥ 18 years of age (median age 57 to 59 y, 51% men) who were initiating warfarin therapy for ≥ 1 month with a target international normalized ratio (INR) of 2 to 3. Initial warfarin dosing based on genotype and clinical factors vs clinical factors alone‡ Outcomes at 28 d
Genotype and Clinical clinical factors factors
% time in therapeutic range
45.2%
45.4%
Event rates Composite secondary outcome§ Any INR ≥ 4 Major bleeding
−0.2% (−3.4 to 3.1)
RRR/RRI (CI)
20%
21%
RRI 0.9% (−21 to 28)
19%
18%
RRI 7% (−17 to 38)
0.8%
Thromboembolism
Mean difference (95% CI)
2.0%
RRR 59% (−31 to 87)
1.0%
0.8%
RRI 27% (−66 to 366)
Nonmajor bleeding
2.5%
4.0%
RRR 38% (−26 to 70)
Mortality
0.4%
0.2%
RRI 109% (−81 to 2171)
‡INR = international normalized ratio; other abbreviations defined in Glossary. RRR, RRI, and CI calculated from control event rates and hazard ratios in article. Results were adjusted for study center and race.
Intervention: Warfarin dosing based on genotype for CYP2C9*2, CYP2C9*3, and VKORC1 and clinical factors (n = 514) or clinical factors alone (n = 501) during the first 5 days of therapy, using a dose-initiation algorithm on days 1 to 3 and a dose-revision algorithm on days 4, 5, or both. Standardized INR-based doseadjustment methods were used after day 5. Outcomes: Primary outcome was percentage of time in therapeutic range (TTR) (INR 2 to 3) from day 4 or 5 to day 28, calculated using the Rosendaal method of standard linear interpolation between successive INR values. Secondary outcomes included a composite of any INR ≥ 4, major bleeding, or thromboembolism; clinically relevant nonmajor bleeding; and mortality. 1022 patients were required to detect a 5.5% difference in TTR (80% power, α = 0.04). Patient follow-up: 94% (modified intention-to-treat analysis for patients with INR data).
Main results Groups did not differ for TTR, any INR ≥ 4, major bleeding, thromboembolism, clinically relevant nonmajor bleeding, or mortality (Table).
Conclusion In patients initiating warfarin therapy, dosing based on genotype and clinical factors or clinical factors alone did not differ for time in therapeutic range at 28 days. *Information provided by author.. †See Glossary.
Sources of funding: National Heart, Lung, and Blood Institute. BristolMyers Squibb provided the warfarin, and GenMark Diagnostics and AutoGenomics lent the genotyping platforms. For correspondence: Dr. S.E. Kimmel, Center for Therapeutic Effectiveness Research, Philadelphia, PA, USA. E-mail stevek@mail. med.upenn.edu. ■
§Composite of any INR ≥ 4, major bleeding, or thromboembolism.
Commentary Pharmacogenetics holds the potential for a personalized approach to clinical management due to the increasing ability to determine genotypes that contribute to medication metabolism and effectiveness. Vitamin K antagonist (VKA) dosing has been a model for the field as 2 of the major genetic determinants of VKA effectiveness are well-described: Sensitivity to VKAs is affected by polymorphisms of the cytochrome P-450 system (CYP2C9) responsible for VKA metabolism and for the gene encoding vitamin K epoxide reductase, which is necessary for the production of activated clotting factors II, VII, IX, and X (1). Thus, knowledge of a patient’s genotype could potentially help guide dosing and prevent adverse events. Previous studies have been limited by small size (2, 3) or observational design (4) and have had mixed results. JC8
© 2014 American College of Physicians
These 3 large, rigorous, randomized trials assessed genotypeguided VKA dosing and have increased our understanding of the utility of these tests. 2 trials found no benefit, and the third found a modest increase in the percentage of TTR but no change in clinical outcomes. Examining differences between the trials can help to assess whether there are any patient groups for whom this strategy may be useful. Verhoef and colleagues assessed acenocoumarol and phenprocoumon rather than warfarin, which may explain the lack of benefit since the CYP2C9 enzyme affects phenprocoumon metabolism less than warfarin (5). The trial by Kimmel and colleagues examined warfarin dosing and enrolled an ethnically diverse population, and over half of patients had VTE. A prespecified subgroup analysis found that genotype-based dosing increased risk for INRs above the therapeutic range more than (continued on page 9) 18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929862/ by a Imperial College London User on 07/24/2017
Therapeutics
In AF or VTE, warfarin dosing by genotype improved time in therapeutic range but not clinical outcomes
Pirmohamed M, Burnside G, Eriksson N, et al; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369:2294-303.
Clinical impact ratings: F ★★★★★✩✩ C ★★★★★✩✩ H ★★★★★★✩ Question In patients initiating warfarin therapy for atrial fibrillation (AF) or venous thromboembolism (VTE), does genotype-guided dosing improve anticoagulation control compared with standard dosing?
Methods Design: Randomized controlled trial (European Pharmacogenetics of Anticoagulant Therapy [EU-PACT] warfarin trial). ClinicalTrials.gov NCT01119300. Allocation: Concealed.*
Intervention: Warfarin dosing based on clinical factors and genotype for CYP2C9*2, CYP2C9*3, and VKORC1 (determined with a point-of-care test) for the first 5 days, using a loading-dose algorithm on days 1 to 3 and a dose-revision algorithm on days 4 and 5 (n = 227) or standard warfarin dosing, with a 3-day loadingdose regimen (≤ 75 y: 10 mg on day 1 and 5 mg/d on days 2 and 3; > 75 y: 5 mg/d on days 1 to 3) and dosing according to usual local clinical practice on days 4 and 5 (n = 228). After day 5, all patients were managed according to local clinical practice. Outcomes: Primary outcome was percentage of time in therapeutic range (TTR) (INR 2 to 3), calculated using the Rosendaal method. Secondary outcomes included any INR ≥ 4, major and minor bleeding events, and thromboembolism.
Blinding: Blinded* (patients). Follow-up period: 3 months. Setting: 3 centers in the UK and 2 centers in Sweden.
Patient follow-up: 94% (with INR data for ≥ 13 d).
Patients: 455 warfarin-naïve patients ≥ 18 years of age (mean age 67 y, 61% men, 72% with AF) who had AF or VTE, were starting anticoagulation with warfarin, and had a target international normalized ratio (INR) of 2 to 3. Initial warfarin dosing based on genotype vs standard dosing in atrial fibrillation or venous thromboembolism† Outcomes at 3 mo
Genotype
Standard Mean difference (95% CI)
% time in therapeutic range
67%
INR ≥ 4.0
27%
37%
Bleeding events
37%
38%
60%
Event rates
7% (3 to 11)
RRR (CI) 27% (2 to 48) 3% (−26 to 28)
NNT (CI) 11 (6 to 143) Not significant
†INR = international normalized ratio; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from control event rates and odds ratios in article. Mean difference was adjusted for study center and indication.
Commentary (continued from page 8) dosing based on clinical factors for black patients, possibly due to variant alleles being less common in black than white patients (6). The effect of the indication for warfarin on the performance of genotype-guided dosing is unknown, although VTE patients are more acutely ill and more likely to start parenteral heparin concurrently than AF patients. The trial by Pirmohamed and colleagues found a modest benefit for genotype-based dosing in time to reach therapeutic range and TTR. This study used warfarin and enrolled 98% white patients, 72% of whom had AF, and compared an algorithm combining genetic and clinical factors with a strategy based on a loading-dose regimen followed by usual practice. Although not specifically powered to assess clinical outcomes, none of the trials found any difference in clinical endpoints, including bleeding. Overall, the 3 trials indicate that genotype-guided dosing may add marginal benefit in the surrogate outcome of obtaining a therapeutic INR for white patients starting warfarin but is unlikely to have any meaningful effect on clinical outcomes. This adds to 18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Main results The main results are in the Table. There were no major bleeding events and 1 thromboembolic event in the standard care group.
Conclusion In patients who are initiating warfarin therapy for atrial fibrillation or venous thromboembolism, genotype-guided dosing improved time in therapeutic range at 3 months, but not bleeding events, compared with standard dosing. *See Glossary.
Source of funding: European Commission Seventh Framework Programme. For correspondence: Dr. M. Pirmohamed, University of Liverpool, Liverpool, England, UK. E-mail [email protected]. ■
previous evidence and recommendations not to use pharmacogenetic testing for warfarin (7). It is uncertain why genotype-guided dosing fails to improve warfarin management, although it probably relates to the availability of the INR value to guide dosing. Pharmacogenetic-based dosing may prove to be more beneficial for medications that have no laboratory or clinical marker to guide dosing or gauge effectiveness. The feasibility of obtaining genotype results in a timely manner may also play a role, as only 45% of patients in the trial by Kimmel and colleagues had results available before the first warfarin dose. However, this information was available before the second dose for 94% of patients. The cost for these 2 assays will vary but generally ranges from $200 to $575 (8). Given the cost and lack of proven clinical benefit, clinicians should forgo genotype testing and concentrate on optimizing processes of care that make warfarin management challenging. These trials confirm the difficulties clinicians face in managing warfarin; despite the study settings, the percentage of TTR was only 45% to 67%, and the median time to reach a therapeutic INR was 21 to 29 days. High-quality warfarin management (continued on page 10) © 2014 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929862/ by a Imperial College London User on 07/24/2017
JC9
Therapeutics
In AF or VTE, acenocoumarol or phenprocoumon dosing by genotype did not affect time in therapeutic range
Verhoef TI, Ragia G, de Boer A, et al; EU-PACT Group. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med. 2013;369:2304-12.
Clinical impact ratings: C ★★★★★✩✩ H ★★★★★★✩ Question In patients who are initiating acenocoumarol or phenprocoumon therapy for atrial fibrillation (AF) or venous thromboembolism (VTE), what are the effects of dosing based on genotype and clinical factors compared with clinical factors alone?
Methods Design: 2 randomized controlled trials (European Pharmacogenetics of Anticoagulant Therapy [EU-PACT] acenocoumarol trial and EU-PACT phenprocoumon trial). ClinicalTrials.gov NCT01119261 and NCT01119274. The trials were combined due to low enrollment. Allocation: {Concealed}*.† Blinding: Blinded† (patients and {data safety and monitoring committee}*). Follow-up period: 12 weeks. Setting: 4 centers in the Netherlands (acenocoumarol and phenprocoumon) and 3 centers in Greece (acenocoumarol). Patients: 548 coumarin-naïve patients ≥ 18 years of age (mean age 68 y, 59% men, 83% with AF) who had AF or VTE and were
starting acenocoumarol (n = 381) or phenprocoumon (n = 167) treatment for ≥ 12 weeks with target international normalized ratio (INR) of 2 to 3. Intervention: Acenocoumarol or phenprocoumon dosing based on genotypes for VKORC1 and CYP2C9 (determined with a point-of-care test) and clinical factors (n = 273) or clinical factors alone (n = 275) for the first 5 to 7 days. Thereafter, dosing was based on INR and local clinical practice. Therapy was initiated as outpatient care in the Netherlands and inpatient care in Greece. Outcomes: Primary outcome was percentage of time in therapeutic range (TTR) (INR 2 to 3), calculated using the Rosendaal method. Secondary outcomes included any INR ≥ 4, major and minor bleeding, and thromboembolism. 200 patients were needed per group to detect a 7% improvement in TTR, with a standard deviation of 23% and a 10% withdrawal rate (80% power, α = 0.05). Patient follow-up: 88% (modified intention-to-treat analysis of patients with ≥ 10 wk follow-up).
Main results The main results are in the Table.
Conclusion Initial acenocoumarol or phenprocoumon dosing based on genotype and clinical factors vs clinical factors alone in atrial fibrillation or venous thromboembolism‡ Outcomes at 12 wk
Genotype and Clinical factors Mean difference clinical factors (95% CI)
% time in therapeutic range
61.6%
INR ≥ 4.0
31%
60.2%
1.4% (−2.8 to 5.5)
33%
6% (−21 to 28)
Event rates
RRR (CI)
Events/person mo
P value
Bleeding events
0.38
0.38
0.94
Thromboembolic events
0.02
0.01
0.62
‡INR = international normalized ratio; other abbreviations defined in Glossary. RRR and CI calculated from event rates in article.
In patients initiating acenocoumarol or phenprocoumon therapy for atrial fibrillation or venous thromboembolism, dosing based on genotype and clinical factors or clinical factors alone did not differ for time in therapeutic range at 12 weeks. *Information provided by author. †See Glossary.
Sources of funding: European Commission Seventh Framework Programme; Swedish Research Council; Swedish Heart-Lung Foundation. LGC provided point-of-care assays. For correspondence: Dr. A.H. Maitland-van der Zee, Utrecht University, Utrecht, The Netherlands. E-mail [email protected]. ■
Commentary (continued from page 9) may include access to a structured anticoagulation clinic, providing appropriate patient education, ensuring frequent INR testing during initiation, real-time dose adjustment in the outpatient setting, using evidence-based approaches to manage periprocedural anticoagulation, and optimizing communication among providers during transitions of care. Andrew Dunn, MD, MPH, SFHM, FACP Mount Sinai Health System New York, New York, USA
JC10
© 2014 American College of Physicians
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18 March 2014 | ACP Journal Club | Volume 160 • Number 6
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