Targeted Research (Jan-Feb-March 2024)

COAGULATION & THROMBOSIS RELATED RESEARCH

1. If Catheter-Directed Thrombolysis Reduced Overall Mortality At The Cost Of An Increased Risk of Minor Bleeding, Would The Safer Oral Fibrinolytic Enzymes Be Better Options?

BACKGROUND: The optimal treatment strategy of patients with pulmonary embolism (PE) (especially those with intermediate risk) continues to evolve and remains controversial.

OBJECTIVES: This study sought to compare the efficacy and safety of anticoagulation (AC) alone, catheter-directed thrombolysis (CDT), and systemic thrombolysis (ST) in patients with acute PE.

METHODS: PubMed and EMBASE were searched for randomized controlled trials or observational studies which compared outcomes of AC alone, CDT, and ST in acute PE. Efficacy outcome was all-cause mortality. Safety outcomes were major bleeding and intracranial hemorrhage (ICH).

RESULTS: We identified 45 studies (17 randomized controlled trials, 2 prospective nonrandomized trials, and 26 retrospective observational trials), which included 81,705 patients. When compared with AC alone, CDT had lower mortality (OR: 0.55; 95% CI: 0.39-0.80) but higher major bleeding (OR: 1.84; 95% CI: 1.10-3.08) and numerically higher ICH (OR: 1.51; 95% CI: 0.75-3.04). ST was associated with no difference in mortality but higher major bleeding (OR: 2.16; 95% CI: 1.38-3.38) and ICH (OR: 2.26; 95% CI: 1.14-4.48) when compared with AC alone. The risk of mortality (OR: 2.05; 95% CI: 1.46-2.89) and ICH (OR: 1.50; 95% CI: 1.13-1.99) was higher with ST when compared with CDT. Findings were similar when analysis was restricted to trials of intermediate risk PE.

CONCLUSIONS: In patients with acute PE, when compared with AC alone, CDT was associated with a lower mortality but higher risk of bleeding. Moreover, CDT had an enhanced safety profile when compared with ST.

Zhang, RS, et al. Efficacy and Safety of Anticoagulation, Catheter-Directed Thrombolysis, or Systemic Thrombolysis in Acute Pulmonary Embolism. JACC Cardiovasc Interv. 2023 Nov 13;16(21):2644-2651. doi: 10.1016/j.jcin.2023.07.042. Epub 2023 Oct 18.

2. Hypercoagulation Predicts Poor Survival In Pancreatic Cancer (And Likely In Other Cancers, Too)

OBJECTIVE: In this study, the relationship between preoperative plasma D-dimer level and overall survival and recurrence free survival were evaluated in patients with curative resection of pancreatic ductal adenocarcinoma.

METHODS: Preoperative plasma D-dimer level of 573 patients with pancreatic ductal adenocarcinoma were collected. The univariate and multivariate Cox hazard models were used to identify independent variables associated with overall survival and recurrence free survival in this study. The Kaplan-Meier method was used to evaluate overall survival and recurrence free survival, and the differences between survival curves were analyzed using the Log-rank test. Continuous variables were presented as $\overline{x}\pm s$, parametric analysis was performed using t-test. Categorical variables were analyzed by means of the chi-square or Fisher’s exact test.

RESULTS: Based on the analysis for the whole study, the results showed that patients in the elevated plasma D-dimer levels had a tendency to have an elder mean age (58.69 ± 8.32 years vs. 63.05 ± 8.44 years, P < 0.001), larger tumour size ≥4 cm (P = 0.006), advanced T stage (P = 0.024), N stage (P = 0.041), Tumor, Node and Metastasis (TNM) stage (P = 0.029) and postoperative complications (P = 0.042) was more likely occurred. Besides, according to the results of Cox multivariate analysis, elevated preoperative plasma D-dimer level was an independent prognostic factor not only for overall survival (Hazard Ratio (HR):1.430, 95% Confidence Interval (CI) (1.163-1.759), P = 0.001) but also for recurrence free survival (HR:1.236, 95% CI (1.018-1.500), P = 0.032).

CONCLUSION: In our study, the elevated preoperative plasma D-dimer level may act as an independent prognostic factor for overall survival and recurrence free survival in patients with pancreatic ductal adenocarcinoma after curative resection. Pancreatic ductal adenocarcinoma patients with elevated preoperative plasma D-dimer level had a worse prognosis than those with normal plasma D-dimer level; and the elevated preoperative plasma D-dimer level may imply heavy tumour burden and provide supplementary information regarding disease status.

Li ZF, et al. Elevated preoperative plasma D-dimer level was an independent prognostic factor for patients with PDAC after curative resection: a retrospective analysis. Jpn J Clin Oncol. 2023 Nov 5;53(11):1058-1067. doi: 10.1093/jjco/hyad090.

Product Q & A From Our Major Sponsor

Q. How can the effects of Boluoke® be reversed in an emergency? Kelly-Anne B. (Scottsdale, AZ)

A: Boluoke® is not an anticoagulant, thus it does not affect the patient’s ability to form a clot (in case of emergency). It is a fibrinolytic agent that enhances the body’s ability to break down fibrin both directly and indirectly.

In all the studies involving only lumbrokinase alone, there’s no increased risk of bleeding. And there have not been any bleeding concerns over the past 30 years of clinical usage. In general, there is no need to stop Boluoke® if the patient is going to have a blood draw, a dental procedure, or minor surgery. For liability reason, we recommend that patients should stop Boluoke® 1 week prior to any scheduled major surgery. However, we know there are doctors who might recommend Boluoke® immediately after surgery (esp. lower body surgeries due to the risk of increased thromboembolism).

Q: My body/kidneys have a very hard time dealing with any type of capsule, gelatin or vegetarian.  I know that if I take capsule contents alone, it will be less effective than if taking in capsule.

That being said, can I take the capsule contents in a tablespoon’s worth of applesauce, a non-fat, non-protein food medium, and still maintain some of the lumbrokinase benefits?

Serrapeptase has been touted as being anti-inflammatory & pain relieving.

Does Boluoke® achieve these same results? Does your research suggest lumbrokinase and other proteolytic enzymes not be taken together?  Thea W.(Unknown location)

A: 1. The capsules used in Boluoke® are acid-resistant vegetarian capsules which are meant to deliver the enzyme to the small intestine, where the absorption occurs. If you do not want to take the capsules, then the best way is to take the contents on an empty stomach so the transit time is shorter. Our internal study shows that this way of dosing is still effective (namely, we can still measure improvement in coagulation balance), though this is not conforming to past clinical study designs.

2. Boluoke® is primarily a fibrinolytic enzyme, though many studies have shown that it can reduce C-RP in cardiovascular patients. At this point, we do not recommend using it as an anti-inflammatory purpose alone because there are other enzymes that can serve that purpose (e.g. serrapeptidase, bromelain, etc).

3. Ideally, we would suggest taking lumbrokinase 30 min before other proteolytic enzymes. However, many doctors have had their patients take Boluoke® together with other enzymes, and there does not seem to be an issue or reduction in efficacy.