206

(Rivaroxaban 158, Apixaban 35, Dabigatran 10, Edoxaban 2 and Apixaban with Dabigatran 1)

794

(Warfarin 787, Acenocumarol 5, Phenindione 1, Warfarin with Fondaparinu× 1)

All patients underwent PEA

One individual underwent BPA for residual CTEPH

Mortality and complication rates during the period between PEA and resumption of oral anticoagulation were excluded from the analysis

Class of anticoagulation was not an independent predictor of survival post-PEA

Sena et al.(2020)

134

(Rivaroxaban)

412

(Warfarin)

Similar between both groups; however, death from bleeding was more in warfarin group

46

(Rivaroxaban 12, Apixaban 11, Dabigatran 1 and Edoxaban 22)

38

(VKA)

1.61 ± 1.01 (DOAC)

2.92 ± 2.87 years (non-DOAC)

13 out of 46 patients in the DOAC group switched from VKA to DOAC due to labile INR and/or bleeding concerns

4 patients underwent PEA (3 in DOAC group and 1 in VKA group)

22 patients in DOAC group underwent BPA

Eight patients received DOACs before and after PEA, while the remaining 12 patients had contraindication to surgery or were on a waiting list

All patients underwent PEA

Abbreviations: BPA=balloon pulmonary angioplasty, CTEPH=chronic thromboembolic pulmonary hypertension, DOAC=direct oral anticoagulants, INR=international normalized ratio, NR=not reported, PEA=pulmonary endarterectomy, VKA=vitamin K antagonists

Evaluating the efficacy and safety of rivaroxaban as a warfarin alternative in chronic thromboembolic pulmonary hypertension patients undergoing pulmonary endarterectomy: A randomized clinical trial

Design

Randomized, parallel clinical trial

N= 96

Objective

To compare the efficacy and safety of rivaroxaban and warfarin in patients undergoing endarterectomy surgery

Study Groups

Warfarin (n= 61)

Rivaroxaban (n= 35)

Inclusion Criteria

Patients who underwent endarterectomy following chronic thromboembolic pulmonary hypertension (CTEPH) diagnosis

Exclusion Criteria

History of allergic to warfarin or rivaroxaban, active bleeding or history of major bleeding in previous three weeks, cerebral aneurysm, dissection of the aorta, history of spinal puncture, blood dyscrasia, uncontrolled systolic blood pressure (≥ 180 mmHg), inflammation and effusion of the pericardium, infective endocarditis, pregnancy and lactation, liver failure (Child-Pugh stages C and D), renal failure (GFR < 30 ml/min), and co-administration with other CYP3A4 and P-glycoprotein inducers or inhibitors

Methods

All patients initially received warfarin prior to surgery, which was discontinued five days before endarterectomy. Enoxaparin was administered three days prior to surgery as bridge therapy at a dose of 1 mg/kg every 12 hours, to be discontinued 24 hours before surgery. After procedure, patients were randomized 2:1 to receive warfarin or rivaroxaban. Patients in warfarin group continued warfarin 24 hours after surgery, with an INR goal of 2-3. Patients randomized to rivaroxaban were administered dose of 15 mg twice daily x 21 days, followed by 20 mg once daily. Rivaroxaban dose was adjusted based on renal function. Other therapeutic regimens were identical between groups. Study was conducted at a single-center in Tehran, Iran. 

Duration

Outcome Measures

Primary: recurrence of thrombosis in the first, third, and sixth months of surgery

Secondary: major and minor bleeding (per International Society of Thrombosis and Haemostasis’s criteria), any-cause hospital readmission, mortality

Baseline Characteristics

Warfarin (n= 61)

Rivaroxaban (n= 35)

Age, years

Male

BMI, kg/m² (interquartile range)

Inferior vena cava filter

21 (34.4%)

Comorbidities

Diabetes

Hypertension

Hyperlipidemia

Chronic obstructive pulmonary disease (COPD)

10 (16.3%)

17 (27.86%)

10 (16.3%)

5 (14.28%)

9 (25.71%)

5 (14.2%)

0.78

0.81

0.78

Results

Endpoint

Warfarin, n/total

Rivaroxaban, n/total

p-value

Thrombosis

Within the first month

Within the first to the third months

Within the third to the sixth months

9/54 (16.6%)

1/35 (2.85%)

3/29 (10.3%)

1/24 (4.16%)

0.52

1

Hospitalization

Within the first month

Within the first to the third months

Within the third to the sixth months

28/54 (51.8%)

6/35 (17.1%)

9/29 (31%)

3/24 (12.5%)

0.06

0.72

Bleeding

Within the first month

Within the first to the third months

Within the third to the sixth months

9/54 (16.6%) Major=1, Minor=8

2/35 (5.7%) Minor=2

1/29 (3.4%) Minor=1

1/24 (4.1%) Minor=1

0.15

1

Mortality

Within the first month

Within the first to the third months

Within the third to the sixth months

13/57 (22.8%)

2/44 (4.5%)

7/31 (22.5%)

0/24 (0%)

0.9

0.53

No significant differences were reported for pulmonary arterial pressure between groups, either before or after surgery. 

Adverse Events

Study Author Conclusions

Rivaroxaban may be as effective as warfarin in treating CTEPH patients after endarterectomy in the short term and can be used as an anticoagulant in these patients. However, studies with long-term follow-ups are needed to consolidate the strategy of treating these patients with rivaroxaban.

InpharmD Researcher Critique

Sample sizes at third and sixth months after surgery were limited due to small sample size remaining at these follow-up points due to high mortality, creating difficulty in assessment of results. Mortality rate was not solely related to cardiovascular causes.  Also, the 2:1 allocation ratio, due to physician's preference for warfarin, resulting in inequality of number of patients in each group. Lastly, this study was conducted at a single hospital in Iran, and standard of care and protocols may vary from the United States. 

Long-term outcome of chronic thromboembolic pulmonary hypertension using direct oral anticoagulants and warfarin: a Japanese prospective cohort study

Design

Prospective, observational, multicenter, database study

N= 956

Objective

To compare the long-term safety and efficacy between Direct Oral Anticoagulants (DOACs) and warfarin for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH)

Study Groups

DOACs (n= 481)

Warfarin (n= 446)

Inclusion Criteria

Patients aged 20 years or older; diagnosed with CTEPH

Exclusion Criteria

Principle investigator or co-investigator judged the patient inappropriate

Methods

Japanese adults diagnosed with CTEPH were enrolled in a registry (CETPH AC registry) for analysis. Patients were grouped as either taking a DOAC or warfarin. The most recent data up to 12 months prior to registration were also collected along with prospective data for the registry. 

Duration

August 2018 to December 2021

Outcome Measures

Primary Outcome: first occurrence of morbidity or mortality event: 

• All-cause death;
• Lung transplantation;
• CTEPH worsening-related rescue pulmonary endarterectomy, rescue balloon pulmonary angioplasty, or start of parenteral pulmonary vasodilator; or
• Reduction (≥15%) in 6-minute walk distance accompanied by worsening of WHO functional class.

Secondary Outcome: the first occurrence of symptomatic venous thromboembolism 

Safety Outcome: the first occurrence of clinical bleeding, a composite endpoint ov major bleeding and/or clinical nonmajor bleeding. 

Baseline Characteristics

Warfarin (n= 446)

Age, years 

Male

Disease Severity

WHO class I

WHO Class II

WHO Class III

WHO Class IV

History of CTEPH-specific treatment

Pulmonary endarterectomy

Balloon pulmonary angioplasty

No reperfusion treatment

36 (7.5%)

252 (52.4%)

207 (43.0%) 

74 (17.0%)

269 (60.3%)

139 (31.2%)

<0.001

0.02

<0.001 

Anticoagulants 

Dabigatran (no. %)

Rivaroxaban (no. %)

Apixaban (no. %)

Edoxaban (no. %)

Prothrombin time- INR 2.0-3.0, (no %)

6 (1.3%)

164 (34.1%)

154 (32.0%)

175 (32.6%)

-

-

-

-

-

187 (42.8%)

NS: not significant 

Results

Endpoint

DOACs (n= 481)

p-value

Morbidity/Mortality (95% CI)

Year 1

Year 2 

Year 3

2.6% (1.4-4.8%) 

3.1% (1.7-5.5%)

4.2% (2.1-8.3%)

3.0% (1.7-5.3%) 

4.8% (2.8-8.0%)

5.9% (3.4-10.1%)

0.52

Bleeding (95% CI)

Year 1

Year 2

Year 3

0.036

Other primary outcome cumulative rates for all-cause death, rescue reperfusion therapy and/or parenteral vasodilator use, and worsening of CTEPH were comparable between the DOAC and warfarin group (all p-values > 0.05).

Secondary outcome cumulative rate was similar between the DOAC and warfarin groups (p= 0.98).

Adverse Events

Study Author Conclusions

The CTEPH AC registry study demonstrated that under the current standard of care, morbidity and mortality events in CTEPH were effectively prevented for up to 3 years regardless of using DOACs or warfarin, while the clinically relevant bleeding rate was lower when using DOACs compared with warfarin.

InpharmD Researcher Critique

This was an observational, registry-based study so the possibility of residual confounding could have affected the data. This was a small, single-country prospective study, a randomized multicounty large-scale study would need to be conducted to validate outcomes. 

Direct Oral Anticoagulants In Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and The Presence of Recent Thrombus During Pulmonary Endarterectomy

Design

Retrospective, single-center, observational, cohort study

N= 405

Objective

To determine if there were differences between patients treated with conventional anticoagulants versus direct oral anticoagulants (DOACs) among patients with chronic thromboembolic pulmonary hypertension (CTEPH) who underwent pulmonary thromboendarterectomy (PEA)

Study Groups

DOAC (n= 166)

Non-DOAC (n= 239)

Inclusion Criteria

Patients diagnosed with CTEPH who underwent pulmonary endarterectomy

Exclusion Criteria

Patients with sarcoma, tissue‐proven primary or metastatic cancer at the pulmonary vessel, septic embolus due to infection, or chronic kidney disease

Methods

This was a retrospective study of patients diagnosed with CTEPH at a single center in California. Patients were bridged from either vitamin K antagonist (VKA) therapy or DOAC before surgery to subcutaneous low molecular weight heparin (LMWH). All oral anticoagulation was stopped 5 days before the intervention. For patients on a DOAC, LMWH started the next day after stopping DOAC; for VKA patients, LMWH was started on the second day after stopping VKA.

Patients were categorized based on normal anticoagulation leading up to PEA: either VKA or LMWH (non-DOAC) or DOAC.

Photos of specimens removed were blindly reviewed by two independent investigators for signs of recent thrombus.

Duration

July 1, 2015 through July 1, 2017

Outcome Measures

Baseline Characteristics

Non-DOACs (n= 239)

DOACs (n= 166)

Age, years

Male

Body mass index, kg/m²

119 (70.5%)

112 (67.5%)

History of deep vein thrombosis

History of pulmonary embolism

126 (52.7%)

233 (97.5%)

85 (51.2%)

159 (95.8%)

Preoperative NYHA functional class

I

II

III

IV

5 (2.1%)

44 (18.4%)

167 (69.9%)

23 (9.6%)

3 (1.8%)

29 (17.5%)

123 (74.1%)

11 (6.6%)

Antiphospholipid syndrome

44 (18.4%)

21 (12.7%)

There were no significant differences in the preoperative characteristics of the patients treated with conventional anticoagulation compared to those treated with DOACs

Results

Non-DOACs group (n= 239)

DOACs group (n= 166)

Recent thrombus

16 (6.7%)

22 (13.3%)

Cardiac output

Preoperative

Postoperative

4.8 ± 1.3

5.6 ± 1.3

4.7 ± 1.3

5.4 ± 1.3

Per an adjusted multivariate analysis, DOAC use was a significant risk factor for thrombus detection post-PEA (odds ratio [OR] 2.43; 95% confidence interval [CI] 1.09 to 5.01). Male gender, Black race, BMI, indwelling catheter, and the total number of CTEPH risk factors were other significant risk factors for thrombus detection.

Antiphospholipid antibody syndrome was not a risk of thrombus detection (OR 0.42; 95% CI 0.13 to 1.41; p= 0.162).

 Thrombus present (n=22)

Adverse Events

Not studied

Study Author Conclusions

Use of DOACs was an independent risk factor for the concomitant finding of recent thrombus during PEA, raising the concern for the use of DOACs in the prevention of recurrent thromboembolism in patients with CTEPH. Further studies are needed to assess the safety and efficacy of DOACs in CTEPH.

InpharmD Researcher Critique

There are limited reports on the safety and efficacy of DOACs in patients with CTEPH. Limitations of this analysis include the retrospective design, which did not evaluate adherence rates and clinical decisions leading to choice in anticoagulation. Inherent bias may exist if non-adherent oral vitamin‐K antagonist (VKA) patients were switched to DOACs to improve treatment adherence and those remaining on VKA tended to be more compliant with medications.

When checking for antiphospholipid syndrome, only anticardiolipin immunoglobulin positive or lupus anticoagulant tests were used; the absence of beta‐2‐glycoprotein antibody testing may have decreased the actual number of patients with APS.