Effect of TIPS Placement on the Survival of Hepatorenal Syndrome Patients: An Instrumental Variable Approach

April 7th 2016

Rowena Crow MD

TIPS - Transjugular Intrahepatic Portosystemic Shunt

AASLD practice guidelines for TIPS procedure:

Recommended treatment for complications of portal hypertension due to severe liver cirrhosis such as

• Variceal Bleeding

• Refractory ascites

• Hepatic Hydrothorax

• Hepatorenal Syndrome - investigatory use pending publishing of controlled trials

3

But…Up to 75 % of patients with severe liver cirrhosis will develop progressive renal failure is known as

Hepatorenal Syndrome aka HRS

• due to decrease in renal perfusion

• severe complication of liver cirrhosis

• very high mortality

Is TIPS a option for treatment?

TIPS rarely done for patients who develop HRS

4

Treatments options for HRS

• Liver transplant - best option, limited availability

• Medical treatment - supportive care, intravenous albumin and vasoconstrictors

• TIPS - minimally invasive procedure to place stent through liver to increase blood flow and correct portal hypertension limited research into effectiveness

Research Question

Does the TIPS procedure improve

in-patient survival in patients with

severe liver cirrhosis who have

developed HRS?

6

HCUP State Inpatient Sample 2000-2012

Discharge data - ICD-9-CM diagnosis and procedure codes, patient demographics, mortality…

Data from 13 states

Extracted data – hospitalized patients with Dx of liver cirrhosis plus Dx of hepatorenal syndrome

7

Exclusion criteria

8

To identify when TIPS is performed as a treatment of HRS plus compatibility with current HRS research

Any patient with concommitent diagnosis of- acute liver failure- chronic kidney disease- infection - SBP, UTI, sepsis, septicemia, bacteremia, pneumonia,

cholangitis- variceal bleeding- Budd Chiari Syndrome (thrombosis)- hypovolemia - abdominal compartment syndrome

Analysis model

Mortalityi = f ( TIPS, Patient Demographicsit, Sx of Liver Cirrhosisit,

Co-morbiditiesit, Hospital Characteristicsi, Yeari, Statei )

There are omitted variables potentially correlated with survival

no clinical data, labs etcno differentiation between HRS type 1 and type 2

9

Instrument Variable Approach

Use a measure that is

• related to probability of treatment - TIPS

• not related to outcome – mortality

TIPS requires specialized Interventional Radiology facilities

• not available at every hospital

IV candidate - differential distance

• The difference between distance from patient’s home to nearest hospital and distance from patients home to nearest TIPS hospital

10

Differential Distance

Assumption 1: a patient whose nearest hospital provides TIPs, is more likely to be offered TIPS procedure - can test this

Assumption 2: the location of a patient’s home is not related to mortality - cannot test - face validity

Aim: chose a measure (IV) that is related to treatment variation in the observational data that is independent of the unobserved patient characteristics

11

Instrument Variable with 2 Stage Residual Inclusion

first stage:

prob(TIPS=1) = Logit( Patientit , Sxit , Co-morbiditiesit ,

Hospital Characteristicsi , Yeari , Statei, Distanceit)

Residualit = TIPSit - prob(TIPS=1)

second stage:

prob(mortality=1) = Logit( TIPSit , Patientit , Sxit , Co-morbiditiesit ,

Hospital Characteristicsi , Yeari , Statei, Residualit)

12

Instrumental variable methods give an estimate of the Local Average Treatment Effect

• The average effect of the TIPS treatment for the observations affected

by the instrument - aka the marginal population

• Who is the marginal population?

• Patients whose likelihood of getting TIPS is effected by the

distance to suitable TIPS facility

• Does not include patients who are ineligible for TIPS

• Does not include patients who are the ‘perfect candidate’ for TIPS13

14

Characteristic All patients

(N=10,052)

TIPS (N=175) Standard Medical

therapy (N=9,877)

Difference

Between the

Means

TIPS (%) 1.7

Inpatient Mortality (%) 34.3 28.6 34.4 5.8

ER Admission (%) 77.3 50.3 77.7 27.4

Ascites (%) 64.8 83.4 64.4 19.0

Hepatic Encephalopathy (%) 39.9 29.7 40.1 10.4

Portal Hypertension (%) 21.0 42.9 20.5 22.4

Teaching Hosp (%) 23.0 51.4 22.5 28.9

Liver Transplant (%) 2.6 6.9 2.5 4.4

Table 1: Patients with HRS 2001 to 2012

15

F-stat = 9.5test for ‘strength’ of IV

Partial R2 = 0.001

Testing Assumption1 - The ‘strength’ of the Instrument Variable

Local Average Treatment Effect

16

Marginal Effect

on Probability of

Death

Logistic Model 2SRI

IV - log(differential distance)

F-test 9.65

TIPS -0.02 (0.037) -0.85 (0.30) **

Residual 0.89 (0.31) ***

* p<0.1; ** p<0.05; *** p<0.01 Standard errors in parenthesis

In the marginal population, patients who receive the TIPSprocedure have a reduction in probability of death of 85%

Sensitivity Analysis - comparison with alternative models

17

Marginal Effect

on Probability

of Death

2SRI IV 2SRI IV

w/o State FE

2SRI IV

ER admissions

excluded

2SRI IV subsample

states with consistent

data 2000 - 2007

TIPS -0.85 (0.30) ** -1.11 (0.29) *** -0.96 (0.43) ** -0.96 (0.31) ***

Residual 0.89 (0.31) *** 1.15 (0.29) *** 1.04 (0.44) ** 1.01 (0.32) ***

F-test IV 9.51 9.56 7.02 9.81

* p<0.1; ** p<0.05; *** p<0.01 Standard errors in parenthesis

Caveats…

Instrument Variable

Assumption 1: Instrument “strength” - F-test of 9.51 slightly less than the literature standard of a value > 10A "weak" instruments,will be poor predictor of treatment

Assumption 2: the location of a patient’s home is not related to mortality location may be related to factors such as access to teaching hospital - effects mortality- teaching hospital variable included in the first stage

18

Conclusions

• IV approach used to give consistent estimates of treatment effect, a

way to account for omitted variable bias

• Large and statistically significant survival benefit found for TIPS

procedure to treat in patients with HRS - in the marginal population

• Survival benefit larger than the estimate from logistic regression

19

20

Questions?