Safe‐Dose Thrombolysis Plus Rivaroxaban for Moderate and Severe Pulmonary Embolism: Drip, Drug, and Discharge

ABSTRACT

Background

Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and rivaroxaban in PE.

Hypothesis

“Safe dose” thrombolysis (SDT) plus new oral anticoagulants are expected to become an appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby drastically reducing hospitalization time.

Methods

Over a 12‐month period, 98 consecutive patients with symptomatic PE were treated by a combination of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours. Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination of heparin infusion.

Results

There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow‐up of 12 ± 2 months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was 1.9 ± 0.2 days.

Conclusions

“Safe dose” thrombolysis plus rivaroxaban is highly safe and effective in the treatment of moderate and severe PE, leading to favorable early and intermediate‐term outcomes and early discharge.

Introduction

Over the last few years, new oral anticoagulants have been introduced that can replace vitamin K antagonists in patients with pulmonary embolism (PE).1, 2 The trials describing these agents have uniformly excluded patients receiving thrombolysis. Though very effective, thrombolysis has not been embraced as routine therapy for symptomatic PE except in very severe cases. Even then, it has been underutilized in the real world for fear of bleeding, specifically the dreaded complication of intracerebral hemorrhage (ICH), which, for tissue plasminogen activator (tPA), has varied between 0.7% and 6.4%.3, 4 Recently we introduced the concept of “safe dose” thrombolysis (SDT), in which half the dose of tPA is given in conjunction with a modified dose of parenteral anticoagulation.5 This approach has been highly safe and effective in the treatment of moderate PE. Rivaroxaban is now approved in the United States for the treatment of venous thromboembolism (VTE). The combination of thrombolysis and rivaroxaban has not been previously reported. This study describes our experience with the combination of SDT and rivaroxaban for the treatment of moderate and severe PE.

Methods

Over a period of 12 months beginning in January 2012, 98 consecutive patients with symptomatic PE were treated by our group with a combination of SDT and rivaroxaban. The use of rivaroxaban was off‐label for most of the duration of this study, until it was approved by the US Food and Drug Administration for this indication in November 2012. This study was conducted in accordance with the amended Declaration of Helsinki. Written informed consent was obtained from all patients, and the study was approved by the institutional review board of A.T. Still University.

All patients had ≥3 new signs and symptoms: chest pain, tachypnea (resting respiratory rate ≥22/min), tachycardia (resting heart rate ≥90/min), dyspnea, oxygen desaturation (resting PO₂ <95%), or elevated jugular venous pressure (≥10 cm H₂O). The onset of symptoms occurred within a mean of 7 ± 3 days (range, 1 day–6 weeks). Diagnosis of PE was made by objective testing with a computed tomographic pulmonary angiogram (CTA) in 86 patients and ventilation/perfusion radioisotope imaging in 12. Moderate PE was regarded as presence of symptoms plus objective evidence of PE, defined as 70% involvement of a pulmonary artery or 2 lobar or 4 segmental branches plus hemodynamic stability. Severe PE was defined as systolic blood pressure ≤100 mm Hg plus all other features of moderate PE; saddle pulmonary embolism; or involvement of >70% of the main pulmonary artery (PA) with thrombus, irrespective of blood pressure. Echocardiography was performed prior to initiation of thrombolysis in 90 patients and within 36 hours post‐thrombolysis in 95 and at 6 months after discharge. Pulmonary artery systolic pressure (PASP) was estimated from the tricuspid valve regurgitant jet velocity using the modified Bernoulli equation as previously described.5 Right ventricular enlargement was defined as a right ventricle//left ventricle ratio of >0.9. Serum brain natriuretic peptide, D‐dimer, and troponin I were measured before SDT in most patients (Table 1). Pulmonary hypertension (PH) was defined as a PASP of ≥40 mm Hg as determined by echocardiography. The patients were evaluated at least daily while in the hospital, within 3 weeks of discharge, and every 6 months thereafter. The mean follow‐up was 12 ± 2 months.

Table 1.

Clinical Characteristics of Patients

Variable	Patients, N = 98
Men	47 (48)
Age, y	56 ± 10
Weight, kg	81 ± 11
BMI	28 ± 3
Previous or concomitant disease
Hypertension	54 (55)
DM	34 (35)
Cardiovascular	32 (33)
CAD	12 (12)
LVEF <40%	5 (5)
Valvular disease	5 (5)
Dysrhythmias	8 (8)
Other	4 (4)
Hypercholesterolemiaa	41 (42)
Pulmonary	30 (31)
COPD	20 (20)
Asthma	5 (5)
Malignancy	4 (4)
Sleep apnea	7 (7)
Renal	10 (10)
Current smoker	35 (36)
Unprovoked PE	54 (55)
Estrogen therapy	8 (8)
Cancer
Active	15 (15)
History	6 (6)
Known prothrombotic state	7 (7)
Previous VTE	16 (16)
Concomitant DVT	52 (53)
D‐dimer elevation	87 of 87 (100)
TnI elevation	52 of 85 (61)
BNP elevation	59 of 80 (74)
RV enlargement	44 of 90 (49)
RV hypokinesia	21 of 90 (23)

Abbreviations: BMI, body mass index; BNP, brain natriuretic peptide; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; DVT, deep venous thrombosis; LVEF, left ventricular ejection fraction; PE, pulmonary embolism; RV, right ventricle; SD, standard deviation; TnI, troponin I; VTE, venous thromboembolism.

Data are presented as n (%) or mean ± SD.

^aHypercholesterolemia indicates total cholesterol >200 mg/dL.

Treatment Regimen

All patients received a modified dose of parenteral anticoagulation with unfractionated heparin. Heparin was given at 70 U/kg as bolus, but not to exceed 6000 U, with subsequent dose adjustment to keep the activated partial thromboplastin time (PTT) at 60 to 100 seconds for 24 hours. While tPA was being infused and for 3 hours thereafter, the maintenance dose of heparin was kept at 8 to 10 U/kg/hour, not to exceed 1000 U/hour. It was subsequently adjusted to reach the target PTT at 60 to 100 seconds. No heparin bolus was given for PTT adjustment. After 24 hours of infusion, heparin was stopped and patients received rivaroxaban at 15 or 20 mg daily, 2 hours after termination of heparin infusion. Patients with creatinine clearance of >30 L/minute received 20 mg of rivaroxaban daily, and those with a creatinine clearance of 15 to 30 L/minute received 15 mg daily. The dose of SDT with tPA has been previously described.5 It was given in parallel with heparin and within 2 hours of admission for most patients. In brief, the patients received 50 mg of tPA, which was given as a 10‐mg bolus by an intravenous push within 1 minute, followed by infusion of the remaining 40 mg within 2 hours. Heparin was the only parenteral anticoagulant administered.

The patients were evaluated for PASP by echocardiography before and after thrombolysis and at 6 months after discharge. Bleeding during and after hospitalization, mortality, and recurrent VTE during follow‐up were also evaluated. Four patients underwent repeat CTA based on the discretion of the attending physician within 24 hours after thrombolysis to assess angiographic improvement.

Statistical Analysis

The data are expressed as mean ± SD. Repeated measures of analysis of variance, with a multivariate approach, were used to compare PASP across the 3 measurement periods. Bonferroni adjustments were used for follow‐up pairwise comparisons. The α criterion per comparison was P = 0.017, 2‐tailed. Statistical analyses were performed with SPSS version 21 (SPSS Inc., Chicago, IL).

Results

There were 84 patients who had moderate PE and 14 who had severe PE, of whom 8 were hypotensive. The clinical characteristics are shown in Table 1. All patients received ≥1 month of treatment with rivaroxaban, as our office provided free samples to patients whose insurance did not cover the drug or who did not have the financial means to pay for it. There were 18 patients who had to change to warfarin (with bridging with enoxaparin) later, due to myalgia in 1 and for insurance reasons in 17. Indefinite anticoagulation was deemed necessary in 63 (64%) patients. The 20‐mg daily dose of rivaroxaban was given in 94 patients. All patients completed a minimum of 4 months of anticoagulation, and 2 were lost to follow‐up. At a mean follow‐up of 12 ± 2 months, 78% of the patients were on anticoagulation. Nine patients were on aspirin, and another 3 were on aspirin and clopidogrel. The median duration of treatment with rivaroxaban for the 18 patients who switched to warfarin was 49 days (range, 32–62 days), whereas it was 392 days (range, 242–485 days) for the remaining patients.

Safety and Efficacy Outcomes

Mortality

There was no in‐hospital mortality. Two patients died of cancer, at 8 and 11 months after discharge, respectively.

Bleeding

No patients experienced either major or minor in‐hospital bleeding. One patient developed hematoma in the psoas muscle while being bridged with enoxaparin to warfarin 2 months after discharge, and another patient who was on rivaroxaban at 20 mg daily developed gross hematuria after being started on high‐dose amiodarone. He was also on aspirin and clopidogrel. None of these events were fatal or required transfusion. In the latter patient, clopidogrel was discontinued and the dose of rivaroxaban reduced to 15 mg daily with resolution of hematuria.

Recurrent VTE

There were no recurrent VTEs in the hospital. Between 5 and 9 months after discharge, 2 patients developed deep venous thrombosis and 1 developed PE. All were receiving warfarin, and 2 had cancer. The international normalized ratio was subtherapeutic in 1. None of the patients on rivaroxaban developed VTE. Pulmonary hypertension was found in 10 patients at 6 months. The changes in PASP are shown in the Figure 1. Complete data were available for 88 patients. The main effect for time was significant, P < 0.001. The mean PASP at initial measurement was 52.8 ± 3.9 mm Hg, which dropped to 32.2 ± 4.4 mm Hg within 36 hours of SDT and to 30.2 ± 4.9 mm Hg at 6 months. Each of the 3 pairwise comparisons was significant, P < 0.001.

Figure 1.

Box plot demonstrating pulmonary artery systolic pressures upon initial measurement, within 36 hours of safe‐dose thrombolysis, and at 6 months. Total number of patients with complete data = 88. Each of the 3 pairwise comparisons was significant (P < 0.001).

Duration of Hospitalization

Six patients with immobility developed PE during the course of a prolonged hospitalization. In 14 others, we were consulted up to 3 days following admission. In the remaining 78 patients whose admission was primarily for PE and who had received SDT and rivaroxaban early on admission, the duration of hospitalization was 1.9 ± 0.2 days. This included 12 of 14 patients with severe PE and 6 of 8 patients with severe PE who were hypotensive on admission.

Discussion

The results demonstrated that a combination of SDT and rivaroxaban is safe and effective in the treatment of moderate and severe PE. It resulted in a rapid decrease in PASP, improvement in clinical status, and early discharge. Recurrent VTE did not occur in patients receiving rivaroxaban and was only noted in patients receiving warfarin. Two of these patients had cancer and 1 had a subtherapeutic international normalized ratio. It is well established that warfarin failure is present in a large minority of patients with cancer, with recurrent VTE developing in as many as 17% at 6 months.6 The bleeding incidents that occurred after discharge were not related to thrombolysis and were noted months later, when rivaroxaban was changed to warfarin or when drug interaction occurred in a patient on additional dual antiplatelet therapy.

In the current study, and based on our experience with SDT, we have not witnessed any bleeding with the tPA dose used.5 Until recently, all existing trials using peripheral venous access have uniformly used full doses of thrombolytic agents. In the recent Pulmonary Embolism Thrombolysis Study (PEITHO), of the 506 patients who were randomized to receive full‐dose tenecteplase and heparin, minor and major bleeding occurred in 32.6% and 6.3% of the patients, respectively, including ICH, which occurred in 10 patients.7 The frequency of ICH was 10× greater than that seen in the control group.7 The results from a multicenter registry reported a major‐bleeding rate of 21.9% in patients with major PE who received full‐dose thrombolysis, as compared with 7.8% receiving standard therapy.8 The International Cooperative Pulmonary Embolism Registry reported a 3% incidence of ICH.9 In a retrospective review of data from 1998 to 2008 on 2,237,600 patients with PE, Stein et al identified 49,500 who had undergone thrombolysis, of whom only 430 (0.9%) developed ICH.10 The dreaded complications of thrombolysis, especially ICH, have dissuaded physicians from embracing this form of therapy, even when there is clear indication for its use. This fear has prompted the use of catheter‐directed thrombolysis (CDT), which uses approximately 20% to 25% of the standard dose of tPA over several hours.11, 12 A recent study using ultrasound‐facilitated CDT demonstrated significant reduction in PASP over 24 hours using ≤20 mg of tPA.12 In the recent Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial using SDT, the PASP also dropped from 50 mm Hg to 35 mm Hg shortly after administration of tPA, which was associated with rapid clinical improvement, early discharge, and no bleeding.5

We believe that full‐dose thrombolysis, such as 100 mg of tPA, is not necessary for treating PE because it is associated with relatively high bleeding rates, especially when performed in the real world and on a large scale. Half the dose is quite effective and eliminates the risk of ICH and major bleeding. The rationale for this recommendation is based on the uniqueness of the lungs and their exquisite sensitivity to thrombolysis. The lungs receive the entire cardiac output and are the center of convergence of all venous flow, no matter from which peripheral vein the thrombolytic therapy is administered. Hence, the thrombolytic‐agent molecules are not “wasted” elsewhere. Furthermore, after the first passage of the thrombolytic agent through the lungs, a repetitious recycle of those molecules occurs by continuously re‐entering the lungs, causing “multiple hits.” The corollary of this concept would apply to CDT. As opposed to every other arterial or venous bed with thrombus that benefits from CDT, in the lungs it would not be necessary. We do not dispute the established efficacy of CDT in the treatment of PE,11, 12 but only suggest that a similar result will be obtained by thrombolysis through the peripheral venous circulation using similar low doses. Even lower doses of what we have used may prove effective. Very low doses of 0.5 to 4 mg of tPA given as bolus have been successfully used in the treatment of intracardiac thrombus and PE during liver transplantation.13

We used a lower dose of rivaroxaban (15–20 mg daily) than that recommended for the treatment of PE in the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism (EINSTEIN‐PE) study.1 That trial used rivaroxaban at 15 mg twice daily for the first 21 days of treating PE, followed by 20 mg daily thereafter.1 The reason for our reduced dosing was that patients requiring thrombolysis were excluded from that and similar studies, and it makes intuitive sense to use a lower dose when tPA is given.

In the 4 patients who underwent CTA before and after thrombolysis, only mild improvement in the extent of thrombus appearance was noted on CTA, despite a significant clinical and subjective improvement. We believe that that there is a clinical/imaging improvement mismatch that occurs in such patients. In other words, angiographic improvement lags behind clinical improvement. Consequently, only mild resorption of thrombus leads to a significant clinical improvement. This is probably due to generation of channels within and around the clot, promoting flow and leading to reduction of PA pressures. In an earlier trial using 50 mg of tPA in 2 hours in 36 patients with PE, this phenomenon was not recognized, as success was defined by angiographic improvement. Because the thrombus still persisted after 2 hours, the investigators gave an additional 40‐mg dose of tPA over 4 hours. This strategy led to minor bleeding in 23 of their patients and major bleeding in 2 patients.14

In the present study, the duration of hospitalization was very short: fewer than 2 days, even in severe PE. This is in sharp contrast to the prevailing hospitalization rates and those related to current trials with new anticoagulants. In the EINSTEIN‐PE trial, the median duration of hospitalization for the rivaroxaban and control arms was 6 and 7 days, respectively.1 In the Efficacy and Safety of Dabigatran Compared to Warfarin for 6‐Month Treatment of Acute Symptomatic Venous Thromboembolism (RE‐COVER) trial, parenteral anticoagulation was given for a mean of 10 days.2 In another study comparing 2 tPA protocols, adjunct intravenous heparin was given for nearly 9 days before and after tPA, presumably in the hospital.15 In a recently published trial evaluating the effects of edoxaban in VTE, intravenous heparin was given for a minimum of 5 days. The median administration of heparin in this trial was 7 days.16

Given the prevailing and projected economic and financial realities surrounding health care, strategies for expeditious and safe treatment of PE are of paramount importance. The approach of “drip, drug, and discharge” reported in this study effectively meets this goal.

Conclusion

We conclude that the combination of SDT and rivaroxaban is highly safe and effective in the treatment of moderate and severe PE, leading to favorable early and intermediate‐term outcomes and early discharge.