Abstract
Direct Oral Anticoagulants (DOACs) can potentially interact with multiple prescription medications. We examined the prevalence of co-prescription of DOACs with interacting medications and its impact on outcomes in patients with atrial fibrillation (AF). Patients with AF treated with a DOAC from 2010 to 2017 at the Mayo Clinic and co-prescribed medications that are inhibitors or inducers of the P-glycoprotein and / or Cytochrome P450 3A4 pathways were identified. The outcomes of stroke/TIA/systemic embolism, major bleeding and minor bleeds were compared between patients with and without an enzyme inducer. Cox proportional hazards model was used to assess association between interacting medications and outcomes. Of 8576 AF patients (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% apixaban, 35.8% rivaroxaban, 25.6% dabigatran), 2610 (30.4%) were on at least one interacting agent: the majority were on an enzyme inhibitor (n=2592). Prescribed medications included nondihydropyridine calcium channel blocker (CCB) (n=1412, 16.5%), antiarrhythmic medication (n=790, 9.2%), anti-depressant (n=659, 7.7%), antibiotic/antifungal (n=77, 0.90%), antiepileptics (n=17, 0.2%) and immunosuppressant medications (n=19, 0.2%). Patients on an interacting medication were more likely to receive a lower dose of DOAC than indicated by the manufacturer’s labeling (15.0% vs 11.4%, p=<.0001). In multivariable analysis, co-prescription of an enzyme inhibitor was not associated with risk of any bleeding [HR 0.87 (0.71 – 1.05), p=0.15] or stroke/TIA/systemic embolism [HR0.82 (0.51 – 1.31), p=0.39]. In conclusion, DOACs are co-prescribed with medications with potential interactions in 30.4% of AF patients. Co-prescription of DOACs and these drugs is not associated with increased risk of adverse embolic or bleeding outcomes in our cohort.
Keywords: DOAC, atrial fibrillation, interaction, enzyme inhibitor
Introduction
The efficacy and safety of direct oral anticoagulants (DOACs) in preventing stroke in atrial fibrillation (AF) patients is well established.1–3 Polypharmacy is common in AF patients and DOACs are prone to both pharmacodynamic and pharmacokinetic interactions with other drugs.4,5 All DOACs are substrates for the permeability glycoprotein (P-gp) efflux transporter, also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1. Inhibitors of P-gp can lead to increased DOAC levels, while inducers can lead to decreased levels.5 Rivaroxaban and apixaban (but not dabigatran) are metabolized through Cytochrome P450(CYP) isoform 3A4, inhibitors of which can increase DOAC levels.5 Drug labeling for rivaroxaban and apixaban recommend avoidance and/or dose reduction in patients taking certain strong dual inhibitors or inducers of CYP3A4 and P-gp. There is no clear guidance regarding combination of DOAC with moderate or mild inhibitors of P-gp and CYP3A4. Published clinical studies to date provide conflicting data on the impact of these medications on outcomes and a recent systematic review highlighted the paucity of data.4,6–8 We sought to investigate the frequency of co-prescription of DOACs with medications with potential interactions and its impact on outcomes in a large single center cohort of AF patients treated with DOACs.
Methods
We identified all patients with AF prescribed a DOAC (apixaban, dabigatran, rivaroxaban and edoxaban) for stroke prevention between 01/01/2010 and 07/01/2017 at the Mayo Clinic, Rochester, Minnesota. We first screened for patients with first prescription of a DOAC and identified those with an AF/flutter diagnosis by International Statistical Classification of Diseases (ICD) 9 and 10 codes (ICD-9 427.31, 427.32 and ICD-10 I48.0- I48.4, I48.91, I48.92) within 3 months of this prescription. Patients with a concurrent diagnosis of deep vein thrombosis or pulmonary embolism were excluded. Patients treated with edoxaban were excluded due to small number (n=17) of patients not allowing for definitive conclusions to be drawn. Demographic and clinical information were obtained from the electronic medical record. The prescribed dose of DOAC was examined to assess whether it adhered to current drug labeling in the USA, based on patient’s renal function, age and weight as previously published.9 Patients were then stratified as receiving correct dose, off-label low dose, and off-label high dose. Co-prescribed medications that were either present at the time of first DOAC prescription or newly prescribed at the time of DOAC initiation were identified. Medication classes of interest included nondihydropyridine calcium channel blockers (CCBs) (diltiazem, verapamil), antiarrhythmics (amiodarone, dronedarone, and quinidine), selective serotonin/norepinephrine reuptake inhibitors (SSRIs/SNRIs) (citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, duloxetine, venlafaxine, desvenlafaxine, levomilnacipran, milnacipran), immunosuppressants (cyclosporine), antifungals (fluconazole, itraconazole, ketoconazole), antibiotics (clarithromycin, erythromycin, rifampin), and antiepileptics (carbamazepine, phenytoin).5
Outcomes of interest included (1) stroke/TIA/systemic embolism, (2) major bleeding events (3) clinically significant non-major bleeding events, and (4) any bleeding event. Stroke / TIA / systemic embolism was defined as clinical diagnosis by a physician based on patient history, physical examination and neuroimaging. To identify these outcomes, we first screened using ICD 9 and 10 codes, followed by manual validation of all outcomes through review of the electronic medical records (Supplementary Table 2). Major bleeding was defined according to the International Society on Thrombosis and Hemostasis.9,10 A clinically relevant non- major bleed is an acute or subacute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least 1 of the following: a hospital admission for bleeding, or a physician-guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. All acute clinically overt bleeding events that did not meet the criteria for either major bleeding or clinically relevant non-major bleeding were classified as minor bleeding. Any bleeding was defined as a composite of major bleeding, clinically significant non-major bleeding and minor bleeding.
Continuous variables are reported using mean ± SD or median, interquartile range as appropriate and compared using the Wilcoxon rank sum test. Categorical variables are presented as number (%) and compared using the chi-square test. The study period for each patient was defined by the start date of the DOAC until date of last follow-up. Variables associated with each outcome of interest were estimated using Cox proportional hazard ratios in univariate analysis. Variables found to be significant in univariate analysis (p<0.05) and some variables that were thought to be clinically relevant were also included in the multivariable Cox regression analysis. A P-value <0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (Cary, NC).
Results
The cohort consisted of 8576 AF patients (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% Apixaban, 35.8% Rivaroxaban, 25.6% Dabigatran). At least one interacting medication was co-prescribed to 2610 (30.4%) patients at the time of DOAC prescription. Median (range) number of co-prescribed medications was 1 (1 – 3). Two and three interacting medications were prescribed to 314 (3.7%) and 25 (0.3%) patients respectively. Enzyme inhibitors formed the majority of co-prescribed medications, with enzyme inducers (Rifampin, Phenytoin and Carbamazepine, N = 18) being rare. The baseline characteristics of the entire cohort and stratified by the presence of interacting medications are presented in Table 1. Patients on an interacting medication were younger, more likely to be female and were more likely to receive a lower dose of DOAC than indicated by the FDA labeling (Table 1). Individual drugs prescribed are presented in Table 2.
Table 1:
Baseline patient characteristics of AF patients prescribed a DOAC stratified by the presence of co-prescribed medications with potential interaction.
| Characteristic | Total (N=8576) | Interacting Medication | P-value | |
|---|---|---|---|---|
| Yes (N=2610) | No (N=5966) | |||
| Age (years) | 69.5 (11.9) | 68.4 (11.8) | 70.0 (11.9) | <0.001 |
| Women | 3008 (35.1%) | 1072 (41.1%) | 1936 (32.5%) | <0.001 |
| White | 8094 (94.4%) | 2486 (95.2%) | 5608 (94.0%) | 0.23 |
| Body-mass index (kg/m2) | 30.4 (6.8) | 31.1 (7.3) | 30.1 (6.6) | <0.001 |
| CHA2DS2-VASc score | 3 (2 – 4) | 3 (2 – 4) | 3 (2 – 4) | 0.51 |
| ATRIA bleeding risk score | 2 (1 – 4) | 2 (1 – 4) | 2 (1 – 3) | 0.78 |
| Charlson co-morbidity index | 2 (1 – 4) | 2 (1 – 4) | 2 (1 – 4) | 0.49 |
| Diabetes mellitus | 2091 (24.4%) | 671 (25.7%) | 1420 (23.8%) | 0.06 |
| Hypertension | 5811 (67.8%) | 1799 (68.9%) | 4012 (67.2%) | 0.13 |
| Hyperlipidemia* | 4633 (54.0%) | 1387 (53.1%) | 3246 (54.4%) | 0.28 |
| Heart failure | 2801 (32.7%) | 942 (36.1%) | 1859 (31.2%) | <0.001 |
| Myocardial infarction | 1026 (12.0%) | 290 (11.1%) | 736 (12.3%) | 0.11 |
| Peripheral vascular disease | 787 (9.2%) | 220 (8.4%) | 567 (9.5%) | 0.11 |
| Aortic atherosclerotic disease | 751 (8.8%) | 181 (6.9%) | 570 (9.6%) | <0.001 |
| Bio-prosthetic valve | 423 (4.9%) | 112 (4.3%) | 311 (5.2%) | 0.07 |
| Anemia | 1051 (12.3%) | 300 (11.5%) | 751 (12.6%) | 0.16 |
| Serum Creatinine (mg/dl) | 1.1 (0.4) | 1.1 (0.5) | 1.1 (0.4) | 0.10 |
| Glomerular filtration rate (ml/minute)** | 84.8 (38.1) | 86.5 (41.3) | 84.0 (36.6) | 0.10 |
| Type of DOAC | <0.001 | |||
| Apixaban | 3312 (38.6%) | 968 (37.1%) | 2344 (39.3%) | |
| Dabigatran | 2198 (25.6%) | 768 (29.4%) | 1430 (24.0%) | |
| Rivaroxaban | 3066 (35.8%) | 874 (33.5%) | 2192 (36.7%) | |
| Off-label DOAC dose | <0.001 | |||
| Low DOAC dose | 1071 (12.5%) | 392 (15.0%) | 679 (11.4%) | |
| High DOAC dose | 202 (2.4%) | 70 (2.7%) | 132 (2.2%) | |
Hyperlipidemia was identified using International Classification of Diseases 9 (272.0–272.4, 374.51) and 10 (E78, H02.61–66) diagnostic codes.
Estimated using the Cockroft Gault method.
Table 2.
Frequency of co-prescription of direct oral anticoagulant and interacting medication
| Medication | Frequency N (%) |
|---|---|
| Non-Dihydropyridine Calcium Channel Blocker | 1412 (16.5%) |
| Diltiazem | 1288 (15.0%) |
| Verapamil | 124 (1.4%) |
| Antiarrhythmic drug | 790 (9.2%) |
| Amiodarone | 633 (7.4%) |
| Dronedarone | 156 (1.8%) |
| Quinidine | 1 (0.0%) |
| Selective Serotonin Reuptake Inhibitor (SSRI) / Serotonin Nor-epinephrine Reuptake Inhibitor (SNRI) | 659 (7.7%) |
| Citalopram | 143 (1.7%) |
| Duloxetine | 115 (1.3%) |
| Fluoxetine | 99 (1.2%) |
| Escitalopram | 98 (1.1%) |
| Venlafaxine | 84 (1.0%) |
| Paroxetine | 78 (0.9%) |
| Sertraline | 27 (0.3%) |
| Desvenlafaxine | 13 (0.2%) |
| Milnacipran | 2 (0.0%) |
| Antibiotic / Antifungal | 77 (0.9%) |
| Erythromycin | 14 (0.2%) |
| Clarithromycin | 4 (0.0%) |
| Rifampin | 1 (0.0%) |
| Ketoconazole | 40 (0.5%) |
| Fluconazole | 17 (0.2%) |
| Itraconazole | 1 (0.0%) |
| Immunosuppressant | |
| Cyclosporine | 19 (0.2%) |
| Antiepileptics | 17 (0.1%) |
| Phenytoin | 12 (0.1%) |
| Carbamazepine | 5 (0.0%) |
Since the prescription of an enzyme inducer was rare, we compared the outcomes amongst patients prescribed an enzyme inhibitor and those without an interacting medication. The median (IQR) follow-up was 0.7 (0.2 – 2.0) years. The incidence of stroke/TIA/systemic embolism, major bleeding and any bleeding event per 1000 patient years of follow-up stratified by the co-prescription of an enzyme inhibitor medication are presented in Table 3. Incidence of major bleeding and any bleeding was lower in patients on an enzyme inhibitor, but no significant difference was noted in the incidence of stroke/TIA/systemic embolism (supplementary material). After adjusting for potential confounders in multivariable analysis, co-prescription of an enzyme inhibitor medication was associated with lower risk of major bleeding, but not any bleeding or stroke/TIA/systemic embolism (Tables 4, 5 and 6). The association between coprescription of an enzyme inhibitor and outcomes was also explored in subgroups of individual DOACs and results of univariate analyses are presented in Table 7.
Table 3:
Incidence of stroke/TIA/systemic embolism and bleeding events stratified by the presence of an enzyme inhibiting medication
| Outcome* | Inhibitor Medication | No Interacting Medication | p-value |
|---|---|---|---|
| Stroke/TIA/systemic embolism | 9.53 (6.41, 13.67) | 9.51 (7.51, 11.89) | 0.468 |
| Major bleeding | 8.80 (5.82, 12.80) | 16.30 (13.58, 19.32) | 0.0003 |
| Any Bleed | 60.20 (51.42, 69.98) | 66.70 (60.92, 72.88) | 0.0042 |
Events per 1000 patient years (95% confidence intervals).
Table 4.
Multivariable analysis of predictors of stroke / transient ischemic attack / systemic embolism
| Variable | Hazard ratio (95% confidence interval) | P-value |
|---|---|---|
| Age | 0.96 (0.93 – 0.98) | 0.0005 |
| Female | 0.85 (0.54 – 1.33) | 0.48 |
| Body mass index | 0.98 (0.95 – 1.02) | 0.42 |
| Apixaban (reference) | ||
| Dabigatran | 1.03 (0.61 – 1.75) | 0.91 |
| Rivaroxaban | 0.81 (0.50 – 1.33) | 0.40 |
| Off-label low dose of DOAC | 1.08 (0.59 – 1.98) | 0.80 |
| CHA2DS2-VASc score | 1.43 (1.24 – 1.65) | <.0001 |
| Interacting medication | 0.82 (0.51 – 1.31) | 0.40 |
| Serum sodium | 0.96 (0.91 – 1.01) | 0.15 |
| Creatinine clearance | 0.99 (0.98 – 1.00) | 0.05 |
Table 5.
Multivariable analysis of predictors of major bleeding
| Variable | Hazard ratio (95% confidence interval) | P-value |
|---|---|---|
| Age | 1.03 (1.00 – 1.06) | 0.03 |
| Female | 0.87 (0.60 – 1.27) | 0.47 |
| Body mass index | 1.02 (0.99 – 1.05) | 0.19 |
| Apixaban (reference) | ||
| Dabigatran | 0.88 (0.53 – 1.45) | 0.61 |
| Rivaroxaban | 1.51 (1.02 – 2.22) | 0.04 |
| Off-label low dose of DOAC | 1.03 (0.62 – 1.73) | 0.90 |
| CHA2DS2-VASc score | 1.20 (1.06 – 1.36) | 0.004 |
| Interacting medication | 0.53 (0.34 – 0.83) | 0.006 |
| Serum sodium | 0.97 (0.92 – 1.01) | 0.1538 |
| Creatinine clearance | 0.99 (0.99 – 1.00) | 0.1904 |
Table 6.
Multivariable analysis of predictors of any bleeding
| Variable | Hazard ratio (95% confidence interval) | P-value |
|---|---|---|
| Age | 1.02 (1.00 – 1.03) | 0.007 |
| Female | 0.82 (0.67 – 0.99) | 0.04 |
| Body mass index | 1.00 (0.99 – 1.02) | 0.85 |
| Apixaban (reference) | ||
| Dabigatran | 1.30 (1.03 – 1.63) | 0.03 |
| Rivaroxaban | 1.49 (1.21 – 1.82) | 0.0001 |
| Off-label low dose of DOAC | 0.93 (0.72 – 1.21) | 0.60 |
| CHA2DS2-VASc score | 1.26 (1.18 – 1.34) | <.0001 |
| Interacting medication | 0.87 (0.71 – 1.05) | 0.15 |
| Serum sodium | 0.97 (0.95 – 1.00) | 0.02 |
| Creatinine clearance | 1.00 (1.00 – 1.00) | 0.54 |
Table 7.
Univariate analysis of outcomes by direct oral anticoagulant type
| Outcome | Odds Ratio (95% CI) | p-value |
|---|---|---|
| Dabigatran | ||
| Stroke/TIA*/Systemic embolism | 0.72 (0.30 – 1.74) | 0.47 |
| Major Bleeding | 0.56 (0.22 – 1.39) | 0.21 |
| Any Bleeding | 1.03 (0.74 – 1.45) | 0.85 |
| Rivaroxaban | ||
| Stroke/TIA/Systemic embolism | 0.87 (0.39 – 1.96) | 0.74 |
| Major Bleeding | 0.41 (0.20 – 0.84) | 0.14 |
| Any Bleeding | 0.67 (0.49 – 0.91) | 0.01 |
| Apixaban | ||
| Stroke/TIA/Systemic embolism | 0.91 (0.46 – 1.77) | 0.77 |
| Major Bleeding | 0.48 (0.24 – 0.95) | 0.03 |
| Any Bleeding | 0.69 (0.50 – 0.95) | 0.02 |
TIA – transient ischemic attack.
Association between use of commonly co-prescribed medications and bleeding outcomes was considered in multivariable analysis. The Cox- proportional hazards model included age, sex, body mass index, type of DOAC prescribed, off-label low dosing of DOAC, CHA2DS2VASc score, ATRIA bleeding risk score, serum sodium and creatinine clearance in addition to the drug under consideration. Co-administration of amiodarone was associated with a trend towards a lower risk of major bleeding [HR 0.40 (0.16 – 1.00), p=0.05], with no significant difference in the risk of any bleeding [HR 0.94 (0.68 – 1.30), p=0.71]. The co-prescription of SSRI/SNRI was associated with a trend towards lower risk of any bleeding [HR 0.62 (0.34 – 1.00), p=0.05], with no significant association with risk of major bleeding events [HR 0.77 (0.31 – 1.90), p=0.57]. Diltiazem was not associated with major bleeding [HR 0.75 (0.43 – 1.32), p=0.32] or any bleeding events [HR 1.00 (0.78 – 1.29), p=0.99].
Discussion
In this large cohort of DOAC treated patients with AF, 30% also received one or more medications with a potential interaction with the DOAC. Commonly prescribed medications were diltiazem, amiodarone and anti-depressants. We report a similar risk of stroke / TIA and systemic embolism in DOAC patients treated with an enzyme inhibitor compared to those on no interacting medication. Importantly, we did not note an increase in risk for bleeding in patients co-prescribed an inhibitor medication. The metabolism of different DOACs, their common drug interactions and the findings of this study are summarized in the Figure.
Figure 1.
Metabolism and elimination of the direct oral anticoagulants, common drug interactions and their effects on outcomes in the current study.
*CYP – Cytochrome P450, **NDP Ca channel blockers – Non-dihydropyridine calcium channel blocker, †SSRI/SNRI – selective serotonin reuptake inhibitor / serotonin norepinephrine reuptake inhibitors.
In this analysis of real world data of DOAC prescription, we show a higher rate of coprescription of interacting medications compared to the randomized controlled trials of DOACs: Jaspers Focks et al reported 20% use of P-gp / CYP3A4 inhibitor in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and Piccini et al reported such drugs in 18% of patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism (ROCKET-AF) trial.4,7 Similar to our study, both of these randomized trials did not find differences in stroke / TIA and bleeding amongst patients on an interacting drug.4,7 We however noted a reduction in the incidence of major bleeding. The observed difference, which is paradoxical to what is expected based on our current understanding of pharmacodynamics of DOAC, may be secondary to the enzyme inhibitor medication group being younger or getting off-label lower DOAC dose more frequently. While the reason for off-label reduction in DOAC dose could not be ascertained retrospectively, this was not associated with outcomes in multivariable analysis, similar to other reports.9,11 The slightly younger age of patients with an interacting medication may be due to concern for adverse effects of combination therapy in the elderly, although this could not be confirmed in this study.
Amiodarone is a moderate inhibitor of P-gp and CYP3A4 and was prescribed to 7.4% of patients. In comparison, the ARISTOTLE and ROCKET-AF trials reported Amiodarone use in 11% and 8% respectively and the Taiwanese national registry reported 21%.12,13 We did not note increase in bleeding events in patients on Amiodarone, with a trend towards reduced incidence of major bleeding events in Amiodarone treated patients. A potential explanation for the noted decrease in major bleeding events could be differential effect of Amiodarone on various aspects of DOAC pharmacokinetics. For example, while co-administration of Amiodarone and Dabigatran leads to higher plasma levels of Dabigatran, this is partially offset by an increase in renal clearance of the drug.5 Individual randomized controlled trials and a meta-analysis of 4 randomized controlled trials comparing DOAC with warfarin also reported similar risk of major bleeding and intracranial bleeding in DOAC patients with and without Amiodarone.12–15 In contrast, Chang et al noted an increased risk of major bleeding in patients on DOAC and Amiodarone compared to DOAC alone in a large cohort from Taiwan.6 This apparent discrepancy in the risk of bleeding complications may be related to differences between Asian and Western populations in the risk of bleeding.16,17 In addition, there was a higher rate of Rivaroxaban use (59%) in the study from Chang et al compared to the current study.
The impact of enzyme inhibition / inducers may vary between different DOACs, particularly with dabigatran which lacks significant CYP interaction. Hirsh Raccah et al reported significant increase in dabigatran levels when coadministered with P-gp inhibitors, while the effect was not as significant on apixaban and rivaroxaban levels.18 Interestingly, we found that risk of bleeding was lower in patients coadministered apixaban / rivaroxaban with an interacting medication. The same was not true for dabigatran. The differential effect of enzyme inhibitors on each DOAC warrants further study.
We present the first detailed analysis of the use of anti-depressant medications, SSRI and SNRI, which are reportedly prescribed to 10 – 15% of the general adult population in the USA.19 Multiple SSRI and SNRI drugs are inhibitors of P-gp20 and Fluoxetine and Fluvoxamine are moderate inhibitors of CYP3A4.21 Serotonin reuptake inhibition can also reduce platelet aggregation, the net effect of which may increase bleeding risk.22 AF patients treated with warfarin and SSRI drugs have been reported to have higher risk of bleeding.23 However, in our cohort of DOAC treated patients, we did not note an increased risk of major bleeding or any bleeding events. Thus, the concomitant use of these newer antidepressants with a DOAC appears to be safe. Diltiazem use has been reported to increase Apixaban level by 40% and has potential interactions with the other DOACs.24 We however did not find an association between the Diltiazem use and stroke or bleeding outcomes.
This study has some limitations secondary to its retrospective observational design. The duration of follow-up was limited. Outcomes were identified using the electronic medical record and under-reporting is possible. The impact of co-prescription of aspirin and non-steroidal antiinflammatory drugs (NSAIDs) on outcomes could not be determined due to difficulty in reliably identifying the use of over the counter medications. The use of certain drugs such as azole antifungals, phenytoin and cyclosporine were rare, likely reflecting physician awareness of the potential for significant interaction with DOAC. Hence, we are unable to comment on the impact of these individual drugs on outcomes. We examined the medications at the time of first DOAC prescription, but not subsequent changes to the patient’s medication use. As a result, the duration of use of an interacting medication is unknown and may have impacted the observed results. Lastly, genotypic variations that can alter drug metabolism through CYP3A4 were not accounted for and could impact the outcomes in this study.
In a real-world cohort of DOAC treated patients with AF, a medication with a potential interaction was frequently co-prescribed. There was no observed association between coprescription of these medications and the occurrence of stroke/TIA and any bleeding. Future investigations with longer followup are needed to confirm safety and efficacy of co-prescribing DOACs with these medications.
Supplementary Material
Funding:
This study was funded by the Mayo Clinic CCaTS grant number UL1TR002377
Disclosures:
Dr. Madhavan reports research support from Bristol Myers Squibb and Pfizer.
Footnotes
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