Goal 2: Reduce Human Disease

Restoring Balance to Stroke Prevention in Older AFib Patients

Improving Tools for Anticoagulation Decision-Making

Submitted by (@cbens0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

AFib increases stroke risk by five-fold and doubles the risk that a stroke will result in permanent disability. While oral anticoagulation (OAC) is highly effective at reducing stroke risk, elderly patients are often under-anticoagulated. This is in part due to an under-appreciation of the stroke risk associated with AFib and the tendency of some health care professionals to prioritize perceived bleeding risk over stroke prophylaxis. Because current bleeding risk assessment tools are imperfect and largely unable to predict patients who are likely to have bleeding complications, they are often not utilized—or if used, do not truly predict which patients are at risk of a bleed. An improved bleeding risk tool is critical to improved risk assessment in the elderly. That bleeding risk tool should then be combined with the stroke risk tool for single risk stratification to streamline anticoagulation decision-making.

Feasibility and challenges of addressing this CQ or CC :

Developing effective integrated risk assessment tools is feasible only if there is consensus on the validity of the clinical information being provided. The approach to this critical challenge is two-fold. First, needed research that improves the reliability of bleeding risk assessment in the elderly should be pursued. Second, stroke and bleeding risk tools should be combined into a single risk stratification tool. This will require significant investment and focus, but the resulting bleeding risk assessment combined with the accepted CHA2DS2-VASc score, would significantly impact the 40 - 60% of patients who are currently not on an anticoagulant and are at increased risk of stroke and death.

Name of idea submitter and other team members who worked on this idea : AFib Optimal Treatment Task Force

Voting

11 net votes
19 up votes
8 down votes
Active

Goal 2: Reduce Human Disease

Will Novel Therapies Create Bleeding Remission HHT and Angiogenic Disorders

Chronic bleeding due to epistaxis and gastrointestinal bleeding telangiectasia in HHT leads to transfusion dependence, iron infusion dependence,

decreased quality of life and premature death.

 

Novel therapies such as pomolidamide, Avastin and pazopanib may be new promising therapies to lead to remission in bleeding and reduce the burden of disease

Submitted by (@mariannes.clancy)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Marianne Clancy, MPA

Voting

1 net vote
2 up votes
1 down votes
Active

Goal 2: Reduce Human Disease

Development of Optimally Hemostatic, Systemically Safe, Platelet Mimetics or Substitutes

What are the knowledge and technological gaps in production, evaluation and clinical translation of donor-independent platelets for transfusions? Specific questions include: a) How can stem or progenitor cells be expanded to maximize platelet production?; b) What are the hemostatically relevant design and function requirements and evaluation metrics for ideal/optimal “biologic” and “synthetic” platelets? c) What preclinical ...more »

Submitted by (@dtriulzi)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Platelets produced from induced pluripotent stem or progenitor (megakaryocyte) cells (biologic production), as well as, manufactured from engineered biomaterials (synthetic production) could address clinical needs of supply issues and transfusion related function and safety concerns. However, there are key knowledge and technology gaps in both approaches, and in corresponding qualitative and quantitative correlation of the platelet products with hemostatic efficacy and safety. One important step is increasing both stem and progenitor cell expansion in culture. A parallel step is to develop synthetic platelet mimetics using biomaterials engineering. Finally, the hemostatic efficacy and safety of the products need to be established in clinically relevant models and patients.

Feasibility and challenges of addressing this CQ or CC :

The above questions can be addressed by establishing high throughput screens for compounds that expand CD34 or CD41 cells or trigger platelet release and ploidy, developing culture methods using 3D scaffolds to mimic bone marrow perivascular niche, using proteomics or RNA-sequencing to reveal molecules critical for terminal megakaryocyte maturation and platelet formation. Large-scale bioreactors can be adapted to test molecules, triggers and conditions for amplifying platelet production. For synthetic platelet mimics, the benefits of integrating natural platelet’s physico-mechanical properties with its hemostatic biochemical properties on synthetic biomaterial platforms, can be studied in vitro. Scaled-up particle fabrication technologies with control over particle geometries and surface chemistries, can be adapted for manufacturing synthetic platelets. Large-scale production of platelets through biologic and synthetic routes would enable studies in animal models with clinically relevant bleeding disorders, to correlate design and dosage with hemostatic function and safety. Subsequently, clinical studies can be carried out in Phase 1 for safety analysis in dose escalation and in vivo kinetics (recovery and survival for biologic, degradation and clearance for synthetic). Phase II studies can evaluate bleeding incidence, transfusion requirements and thrombotic events in a controlled population of thrombocytopenic patients under-doing chemotherapy or stem cell transplantation.

Name of idea submitter and other team members who worked on this idea : NHLBI 2015 State of the Science in Transfusion Medicine

Voting

20 net votes
38 up votes
18 down votes
Active

Goal 2: Reduce Human Disease

Duplicate

Duplicate

Submitted by (@dtriulzi)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

duplicate

Feasibility and challenges of addressing this CQ or CC :

duplicate

Name of idea submitter and other team members who worked on this idea : duplicate

Voting

-12 net votes
3 up votes
15 down votes
Active

Goal 2: Reduce Human Disease

Need to assess a new method of warfarin management vs. new oral anticoagulants in patients with atrial fibrillation

The two obstacles to warfarin therapy (keeping the INR in range and the associated hassles of frequent lab visits) can be eliminated by INR self testing and online "virtual clinic" monitoring and management (as demonstrated in six small studies. Achieving an INR percent time in range of approximately 75% to 80% is associated with a 50% or lower rate of thromboembolism and major bleeding. The studies of new oral anticoagulants ...more »

Submitted by (@bussey)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

If the ease and convenience of INR self testing, when combined with online virtual clinic management, can double the safety and efficacy of warfarin therapy, this form of therapy will benefit millions of patients with atrial fibrillation world wide. By extrapolation, this mode of therapy may also benefit millions of patients at risk of venous thrombosis, myocardial infarction, and stroke.

Feasibility and challenges of addressing this CQ or CC :

This issue would require a prospective randomized control trial in moderate to high risk patients with atrial fibrillation to compare warfarin managed with such a system vs treatment with one of the new oral anticoagulants. Additional issues could be addressed if the study also included a warfarin arm with traditional management and/or an arm that involved monitoring of the new agent. The projected impact of the new warfarin management method on a composite end point of stroke, systemic embolism, major bleed and death is large enough (30 to 60 fewer events per 1,000 patients per year) that the sample size would be much smaller than the trials used to evaluate the new agents vs warfarin in atrial fibrillation.

Name of idea submitter and other team members who worked on this idea : Henry I. Bussey, Pharm.D.

Voting

73 net votes
93 up votes
20 down votes
Active

Goal 2: Reduce Human Disease

What new methods of platelet preparation, processing, and storage are needed for hemostasis in various clinical conditions?

The limitations of 5-day 22˚ C storage significantly impacts platelet availability. It is critical that we develop new methods of collection, processing, storage to extend the storage time of platelets, and evaluate the use of whole blood. The attributes of these products must be understood to optimally alignment product attributes, clinical efficacy and safety with hemostatic needs in a variety of clinical states. Specifically, ...more »

Submitted by (@bldbuddy)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Limitations of current storage methods challenge our ability to meet the increasing demands of cancer chemotherapy and complex surgeries as well as provide platelets to remote areas where trauma frequently occurs. Platelets are transfused to prevent or control bleeding without robust translational or clinical trial evidence of efficacy and safety. In patients with hypoproliferative thrombocytopenia receiving chronic platelet transfusion predominantly for prophylaxis, post-transfusion increments, survival time, and durable hemostatic efficacy are important; however, platelet transfusion alone does not prevent bleeding. The overall state of hemostasis, the endothelium and donor characteristics that affect platelet quality may be important considerations in selecting the best platelet product tailored to individual patients. Better laboratory and clinical measures of platelet function, efficacy and safety are essential for best use of these limited resources. These outcomes should span and link in-vitro testing, animal models, and clinical effects such as thrombotic events, immune, hemostatic, and endothelial effects. Extrinsic, recipient factors (e.g., immune deficiency, platelet or endothelial dysfunction) and intrinsic factors (e.g., donor specific or platelet preparation) should be considered. Systematic analysis of recipients and donors should be broad and include considerations of glycomics, metabolomics, proteomics, genomics, in vivo microscopy, and advanced imaging.

Feasibility and challenges of addressing this CQ or CC :

Radiolabeled platelet recovery and survival methods are well established and feasible to perform at several centers within the US. Currently 4-6 million units of platelets and whole blood are transfused per year. It is very feasible to conduct clinical trials that compare methods of platelet preparation, processing, and storage in children and adults who require platelets for either prophylaxis or active bleeding. Multiple research networks that focus on both pediatric and adult transfusion medicine are motivated to perform the pre-clinical and clinical trials required to establish improved efficacy and safety of platelet-containing blood products.

Name of idea submitter and other team members who worked on this idea : Terry Gernsheimer, University of Washington, for the 2015 NHLBI State of the Science in Transfusion Medicine

Voting

14 net votes
34 up votes
20 down votes
Active

Goal 3: Advance Translational Research

Novel Mechanism for Clinical Trials of New Pro-Hemostatic Agents in Hemophilia

There are new exciting novel pro-hemostatic therapeutics in early phase clinical trials for hemophilia and hemophilia inhibitor patients. Yet, it is difficult to design randomized trials to compare these agents, or compare them with standard treatment, given the small sample size and competing studies for such patients. It is critical to develop novel approaches to compare new agents in rare populations. For example, ...more »

Submitted by (@ragni01)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Should rare disease-specific strategies for clinical trials be developed, it would revolutionize the approach to study of not only rare disease populations, but all disease groups, no matter their size. If validated, rare disease-specific clinical trial strategies, would potentially reduce the cost, time, patient burden, and research effort to conduct clinical trials. If validated, consideration could be given to drug licensure earlier in the trial process, with a requirement for all such trials to initiate and continue ongoing data collection post-licensure for safety and efficacy.

Feasibility and challenges of addressing this CQ or CC :

Novel statistical methodologies are greatly needed to help with rare disease research. NHLBI might consider a grant mechanism RFA to encourage development of novel clinical trial strategies utilizing smaller sample size. The proof would be to develop the methodology as part of a feasibility study, and then, if feasible, adapt the novel approach to development and conduct of a clinical trial in a rare disease clinical tria,l to test the concept.

Name of idea submitter and other team members who worked on this idea : Margaret V. Ragni, MD, MPH (aspects discussed with Don Brambilla PhD.

Voting

6 net votes
15 up votes
9 down votes
Active

Goal 2: Reduce Human Disease

Balancing Risks and Benefits: How Do Clinical Guidelines in Cardiovascular Medicine Promote the Health of an Individual?

Much of the hopes for precision medicine (as outlined Dr. Dr. Collins) are based on deriving large amounts of genomic, proteomic, epigenomic and metabolomic data on large cohorts of patients. It will take decades to build these cohorts and even more time to analyze them and derive specific conclusions on how these will help individualize treatments. However, there is a pressing need for how to individualize contemporary ...more »

Submitted by (@jalees)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Decisions on whether or not to place a patient with atrial fibrillation on chronic anticoagulation or on statin therapy are often based on guidelines and cardiovascular risk calculators.

 

Patients with a higher risk of stroke are more likely to receive anticoagulation and patients with a higher risk of a myocardial infarction are more likely to receive statin therapy.

 

However, these cardiovascular risk calculators do not really take into account the potential side effects and impact on the lifestyle of the patients.

 

Physicians will stop anticoagulation in a patient with atrial fibrillation if the patient has suffered a life-threatening bleed but there are no specific evidence-based guidelines as to how one should proceed if the bleeding is minor.

 

it is easy to compute the cardiovascular risk and overall mortality benefit of placing a patient on statins but how does one factor in the impact that statins have on the quality of life of an individual?

 

Developing novel evidence-based approaches to individualize therapies that factor in cardiovascular benefits as well as potential side effects and diminished quality of life could have a major impact on appropriately using treatments and reduce the arbitrariness of some medical decisions.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

Voting

1 net vote
1 up votes
0 down votes
Active

Goal 2: Reduce Human Disease

How should platelet (PLT) transfusions be used to treat active bleeding?

Multiple randomized controlled trials have been performed to evaluate the use of prophylactic PLT transfusions in non-bleeding, thrombocytopenic hematology-oncology patients. However no high-quality data exist to guide PLT transfusions in actively bleeding patients inclduing pediatric and adult medical and surgical patients. After hematology-oncology patients, cardiac surgery patients are the next largest group of PLT ...more »

Submitted by (@bldbuddy)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

PLT count is almost always the only laboratory result considered in deciding to transfuse PLTs. But PLT counts provide no information about PLT hemostatic function and its contribution to bleeding. A variety of in vitro coagulation tests have been developed: viscoelastography, whole blood PLT aggregometry, etc. But while testing-based transfusion algorithms may reduce blood product utilization, it has not been established that any in vitro test can either predict or help reduce bleeding. There is a gold standard method to assess clinical efficacy of transfused PLTs: incidence of grade 2 or higher bleeding in clinical trials of thrombocytopenic hematology-oncology patients receiving prophylactic PLT transfusions. No analogous gold standard of PLT hemostatic efficacy exists for therapeutic PLT transfusions to treat active bleeding. There is a pressing need to develop such a standard. Establishing reliable methods for evaluating the effects of PLT transfusion in actively bleeding patients will improve our understanding of how different factors (storage conditions, pathogen reduction etc.) affect the functional performance of PLTs.

Feasibility and challenges of addressing this CQ or CC :

PLT transfusions are administered routinely to support bleeding pediatric and adult medical and surgical patients. Opportunities to conduct clinical trials in various settings (cardiac surgery, neurosurgery, orthopedic surgery, trauma, etc.) are widely available. PLT transfusion is commonly used to support bleeding patients receiving perioperative supportive therapies such as extracorporeal membrane oxygenation (ECMO). These clinical situations represent critical opportunities to improve the care of bleeding patients. This approach will simultaneously facilitate comprehensive evaluation and validation of both current and novel in vitro tests of hemostasis. If a given in vitro test were reproducibly shown to correlate strongly with bleeding reduction caused by PLT transfusion, then by definition that would be a clinically meaningful test. Finally, this line of inquiry will allow assessment of the adverse effects of PLT transfusion in bleeding patients.

Name of idea submitter and other team members who worked on this idea : Terry Gernsheimer, University of Washington, for the 2015 NHLBI for the State of the Science in Transfusion Medicine

Voting

30 net votes
44 up votes
14 down votes
Active