Is GI bleeding a worthwhile treatment indication?

Considering the recent very unpleasant price movement thatwas mainly triggered by the LVAD trial results I decided to do some in depthresearch about the medical and financial ramification of GI bleeding to get abetter understanding of the approval probability.

I was especially trying to look at the topic from an healthcare financial burden point of view, which is a little out of my main area ofexpertise (biomedical research). Therefore, I would ask everyone to criticallyreview the topic yourself and welcome any kind of constructive feedback.

Medical significanceof GI bleeding in the setting of LVAD

The main thing to note here is that there is no significantassociation between the occurrence of GI bleeding and overall survival in LVADpatients [1, 2].This most likely is because medical care for GI bleeding, mostly endoscopictherapeutic interventions, is very successful (96.2%) with a relatively low complicationrate of 6.6% [3].However, patients suffering from GI bleeding have asignificant increased risk of subsequent thromboembolic events [2].Thromboembolic events include stroke, transient ischemic attack, hemolysis orpump thrombosis/power surge, which by itself are also not associated withoverall survival [2]. Needless to say they still are a very undesirable outcome for the patients. I guesseveryone that knows someone that suffered a stroke will agree to that.

Beside these increased risks of other adverse events, themain consequence of GI bleeding is re-hospitalization that are often followedby blood transfusions [1]and have a median length of 6 days [4].These increase the risk of allosensitization, which is especially problematicfor transplant candidates [1].Importantly our trial showed that and I quote from the ASXannouncement “overall time to transplant was similar between the two groups,despite a non-significant increase in anti-HLA class I antibodies in the MPCgroup (26% vs 9% in controls)” 

Overall, I can definitely see why the FDA is a clinicallymeaningful outcome. 

Financialsignificance of GI bleeding

To analyse this we need to look up a few facts, which I triedto draw from recent sources.

• According to the Mesoblast presentation, thereare ~4,500 – 5,500 LVAD patients.
• GI bleeding occurs in approximately 20to 30% of patients with CF-LVADs with some reports showing GI bleedingin up to 61% of patients [1]. It is noteworthy that continuous flowLVADs have a survival benefit but a GI bleeding disadvantage compared to pulsatileflow LVADs and are now the FDA approved standard [5]. Therefore, older data that reports GIbleeding might show lower GI bleeding rates than observed with the new devices!
• Re-bleedingrates have been reported to be 30%-40% with some reports showing re-bleedingrates up to 72% [1]
• Recently,hospitalization associated with GI bleeding has been reported to be 31.4% withre-bleeding related re-hospitalizations of 56% for one, and 25% for multiplere-hospitalizations [6]. 
• Overall GI bleeding results in hospitalization costs of $38,655and an average net loss of income for the patient of $12,557 [4]
• According to the presentation of the LVAD trial results ourproduct reduces GI bleeding hospitalizations by 2/3 (0.07 vs 0.21) or 66.6%.

Using a conservative estimation of the above facts, with 4500 patients per annum, GI bleeding hospitalizations of 25%with re-hospitalization rates for a second admission of 35% and multiple admissions of 25% (multipleadmissions will be calculated as a single 3ed admission) we can come up withthe following estimates 

• Total GI bleeding associated hospitalization costs to $69.58mill
• Total GI bleeding associated hospitalization loss of income to $31.78mill
• For a total financial burden of $101.36mill 

Considering the reduction in GI bleeding following treatmentwith MPC-150-IM it has the potential to:

• Reduce GI bleeding associated costs to $39.1mill
• Reduce the GI bleedingassociated hospitalization loss of incometo $21.17mill
• For a total remaining financial burden of $41.1mill   

Looking at the MPC-150-IM treatment, a single injection of150 million cells, we can use the current TEMCELL price in Japan as guidance (US$7,079 per bag of 72 million cells) to estimatethe cost per treatment to be $14,748

Because our MPC-150-IM will be a preventive treatment allpatients will have to be treated resulting in therapy costs of $66.37mill, which together with theremaining GI bleeding hospitalizations results in a total treatment cost of $96.85mill.

Therefore, the totaladditional cost per patient is $6059.2If you consider thefinancial burden (cost + loss of income), the costs are $1355.1 per patient. 

Considering the conservative use of GI bleeding rates andre-hospitalization rates there should be financial upside left. If we would usethe rates of the latest study [6]costs per patient would be less than $2300 per patient with a cost saving ofmore than $3500 if we account for the loss of income.

Additionally, as statedbefore, GI bleeding is also associated with increased thromboembolic events.These events can also result in significant costs as is exemplified by hemolysis,which results in hospitalization costs of $141,791 per stay [4].

Overall, I think thatthe medical and financial benefits are significant and should strongly favor FDAapproval and authorization of reimbursement for MPC-150-IM, making it a successful treatment for patients, healthcare providers and Mesoblast in the future

References

1. Cushing, K. and V. Kushnir, Gastrointestinal Bleeding Following LVADPlacement from Top to Bottom. Dig Dis Sci, 2016. 61(6): p. 1440-7.

2. Stulak, J.M., etal., Gastrointestinal bleeding andsubsequent risk of thromboembolic events during support with a left ventricularassist device. J Heart Lung Transplant, 2014. 33(1): p. 60-4.

3.Taylor, C., etal., 535 OUTCOMES OF GASTROINTESTINALBLEEDING IN PATIENTS WITH LEFT VENTRICULAR ASSIST DEVICES: A TERTIARY CARECENTER EXPERIENCE. Gastrointestinal Endoscopy, 2018. 87(6): p. AB93.

4. Schmitt, A.A., etal., Cost Analysis of Leading Causes forLVAD Patient Readmissions. The Journal of Heart and Lung Transplantation,2015. 34(4): p. S336.

5. Trinquero, P., etal., Left Ventricular Assist DeviceManagement in the Emergency Department. West J Emerg Med, 2018. 19(5): p. 834-841.

6. Welden, C.V., etal., Clinical Predictors for RepeatHospitalizations in Left Ventricular Assist Device (LVAD) Patients WithGastrointestinal Bleeding. Gastroenterology research, 2018. 11(2): p. 100-105.