# Presentation: 512712

## Expanded Indications and Claims for Guidant CRT-D Devices

**Owen P. Faris, Ph.D.**
**Scientific Reviewer**
**U.S. Food and Drug Administration**
**July 28, 2004**

## FDA Review Team

- Lead:		Owen Faris, Ph.D.
- Statistical:	Barbara Krasnicka, Ph.D.
- Clinical:		Scott Proestel, M.D.
- 				Ileana Piña, M.D.
- Bioresearch Monitoring:	Rachel Solomon 					MHS, FAHA

## Regulatory Background

- September 8, 1999: Agreement letter for COMPANION clinical trial sent to sponsor from FDA
- January 20, 2000: First patient enrolled in COMPANION
- May 2, 2002: Guidant CONTAK CD (CRT-D) approved by FDA
- November 30, 2002: COMPANION trial stopped
- January 26, 2004: Guidant CONTAK TR/RENEWAL TR (CRT-P) approved by FDA
- March 26, 2004: Request for expanded indications and new claims for Guidant’s CRT-D devices based on results from COMPANION submitted to FDA

## COMPANION Agreements

- Inclusion and exclusion criteria
- Primary and secondary hypotheses
- Statistical analysis plan
- Statistical plan would not support CRT-D vs. CRT-P comparisons
- To address multiplicity, consistency across primary and secondary endpoints was required to evaluate any one endpoint

## Changes from Current Indication

- 	The sponsor’s proposed indication requests the following changes based upon results from the COMPANION clinical trial:
- Expanded indication to include the entire population described in COMPANION
- New Claims
- Primary composite endpoint benefit
- Mortality benefit

## Proposed Indication

- Guidant Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) are indicated for patients with moderate to severe heart failure (NYHA III/IV) who remain symptomatic despite stable, optimal heart failure drug therapy, and have left ventricular dysfunction (EF </= 35%) and QRS duration >/= 120 ms.
- Guidant Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) have demonstrated the following outcomes in the indicated population specified above:
- Reduction in risk of all-cause mortality _or_ first all-cause hospitalization
- 	*Note:  Hospitalization is defined as administration of IV **	**inotropes or vasoactive drugs > 4 hours (outpatient or **	**inpatient), **	**or admission to a hospital that includes or extends beyond a **	**calendar date change.*
- Reduction in risk of all-cause mortality
- Reduction of heart failure symptoms

## Scope of FDA’s Review

- COMPANION primary and secondary endpoint results
- COMPANION hospitalizations and adverse events
- Consistency with pre-specified clinical and statistical plans
- Presentation of data in device labeling

## Barbara Krasnicka, Ph.D.
FDA, CDRH
Division of Biostatistics

- Barbara Krasnicka, Ph.D.
- FDA, CDRH
- Division of Biostatistics

## Study Design 

- Objective of the COMPANION study was a comparison of:
- OPT (Optimal Pharmacologic Therapy)
- CRT-P (OPT plus Cardiac Resynchronization Therapy)
- CRT-D (OPT plus CRT + Defibrillator therapy )

## Study Design

- Prospective
- Three arms
- Multi-center (128)
- Randomized
- Group sequential design
- Trial was planned to stop after 1000 primary endpoint events (mortality or hospitalization) would be identified

## Study Design 

- It was expected that, compared to OPT alone, CRT-D could reduce
- combined all-cause mortality and all-cause hospitalization  (primary effectiveness endpoint)
-  all-cause mortality and cardiac morbidity (secondary effectiveness endpoints)
- Safety Endpoint: None

## Data Collection and Quality

- Primary effectiveness endpoint was modified three times
- All-cause hospitalization
- Original definition
*	*admission to a hospital for any reason and endpoint would include emergency room visits (or unscheduled office visits) that result in treatment with IV therapy
-  Last version of the definition
- 	hospitalization for which the discharge date was different from the admission date or hospitalization longer than 4 hours during which patient received IV therapy

## Data Collection and Quality

- Hospitalization Case Report Form included data on the admission and discharge dates not taking into account exact time
- Capture of the hospitalization events longer than 4 hours during which patient received IV therapy was based on the duration of the IV therapy
- Case Report Forms  missing for some hospitalizations

## Data Quality 

- Study stopped in December, 2002
- 941 “potential” primary endpoint events had been submitted
-  Many withdrawals from the study
- Withdrawal rates at 12 months were different for the two groups:
- OPT group - 21% (64 patients)
- CRT-D group -  4% (25 patients)
- FDA is concerned that worsening of patients’ health status was probably the reason for withdrawals

## Withdrawn patients re-consented to collect endpoints data and vital status
FDA is concerned that post-withdrawal information regarding hospitalizations may be unreliable 

- FDA is concerned that post-withdrawal information regarding hospitalizations may be unreliable

- Data Quality

## Statistical Analyses

- Combined all-cause mortality or all-cause hospitalization and all-cause mortality
- Kaplan-Meier method, Log-rank test or Wilcoxon test
- Cox model
- Cardiac morbidity, adverse events
-  Exploratory analyses

## All-cause mortality and all-cause hospitalizationKaplan-Meier estimates of the event-free functions

## All-cause mortality and all-cause hospitalization

- Tentative assumptions:
- Quality of Data set was good
- The primary endpoint (all-cause hospitalization) was not changed
- Censoring was non-informative, i.e., the censoring was independent of occurrence of an event

## For combined all-cause mortality and all-cause hospitalization endpoint: 
The event-free time of some patients could be censored as a result of a worsening of their health status, i.e., censoring may be informative
Fundamental assumption for the survival analyses may not be satisfied.  

*The event-free time of some patients could be censored as a result of a worsening of their health status, i.e., censoring may be informative*
- Fundamental assumption for the survival analyses may not be satisfied.

- All-cause mortality and all-cause hospitalization

## All-cause mortality and all-cause hospitalization

| Time | CRT-D (N=595) |  | OPT (N=308) |  |
| --- | --- | --- | --- | --- |
|  | Failure | # of Available | Failure | # of Available |
|  | Rate | Patients | Rate | Patients |
| 30 days | 0.12 | 516 | 0.17 | 241 |
| 60 days | 0.22 | 458 | 0.26 | 212 |
| 200 days | 0.45 | 307 | 0.47 | 126 |
| 400 days | 0.59 | 184 | 0.69 | 56 |

- Kaplan-Meier estimates of the failure rates

## Survival functions for the CRT-D and OPT groups are different
P value = 0.025 (Wilcoxon test)
Under assumption of proportionality, Cox model supplied for the
CRT-D vs. OPT hazard ratio 
Point estimate: 0.81  (i.e., 19% reduction in the relative risk)
95 % confidence interval (0.68,0.96) 
P value  = 0.015
Proportional hazards assumption may not be satisfied in this case

- P value = 0.025 (Wilcoxon test)
- Under assumption of proportionality, Cox model supplied for the
- CRT-D vs. OPT hazard ratio
- Point estimate: 0.81  (i.e., 19% reduction in the relative risk)
- 95 % confidence interval (0.68,0.96)
- P value* * = 0.015
- Proportional hazards assumption may not be satisfied in this case

- All-cause mortality and all-cause hospitalization

## Results of the statistical analysis may be problematic because:

The primary effectiveness endpoint definition was changed during the study

- The primary effectiveness endpoint definition was changed during the study

- All-cause mortality and all-cause hospitalization

## The assumptions underlying the statistical methods used may not be satisfied
Censoring may be informative 
	The censoring may not be independent on the occurrence of the event because some patients withdrew from the study due to worsening of their health status
The hazard functions and the Schoenfeld residuals indicate that the proportionality assumption may not be valid

- Censoring may be informative
- 	The censoring may not be independent on the occurrence of the event because some patients withdrew from the study due to worsening of their health status
- The hazard functions and the Schoenfeld residuals indicate that the proportionality assumption may not be valid

- All-cause mortality and all-cause hospitalization

## All-cause mortality 

- Statistical analyses for all-cause mortality secondary endpoint raises similar statistical concerns as the primary effectiveness endpoint analyses

## Kaplan-Meier estimates of the survivor functions for all-cause mortality

## Kaplan-Meier estimates of the survivor functions and their confidence limits for all-cause mortality

## Death rates (Kaplan-Meier estimates) for the CRT-D and OPT groups

| Time | CRT-D |  | OPT |  |
| --- | --- | --- | --- | --- |
|   | Death Rate | # of Active Pts. | Death rate | # of Active Pts. |
| 10 days | 0.008 | 590 | 0.00 | 306 |
| 30 days | 0.012 | 581 | 0.0098 | 301 |
| 60 days | 0.019 | 573 | 0.033 | 291 |
| 200 days | 0.074 | 510 | 0.0976 | 250 |
| 400 days | 0.125 | 387 | 0.2164 | 167 |
| 600 days | 0.197 | 169 | 0.3104 | 63 |

## All-cause mortality

- Survival functions for the CRT-D and OPT groups are different
- P value = 0.003
- CRT-D vs. OPT hazard ratio (Cox model)
- Point estimate: 0.64  (i.e., 36% reduction in the relative risk)
- 95 % confidence interval (0.48,0.86)
- P value* * = 0.003

## All-cause mortality

- The statistical results may be problematic because:
- The assumptions underlying the statistical methods used may not be satisfied
- 	Hazard functions and the Schoenfeld residuals do not reasonably support the proportionality assumption

## Secondary Endpoint - Cardiac Morbidity

|   | CRT-D | OPT |
| --- | --- | --- |
| Hospital | 0 | 2 |
| Out of hospital | 5 | 1 |
| Total | 5 | 3 |

- Sponsor considered only cardiac morbidity events that         	occurred in hospitals
- However, cardiac morbidity events may occur out of hospital
-    Cardiac death during the first 30 days after randomization

## Adverse Events

- Sponsor’s definition:  “*undesirable clinical outcomes and included device-related events as well as events related to the patients' general condition”*

## Adverse Events during 6 Months after Randomization

|   | CRT-D (N=595) |  |  | OPT (N=308) |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Time Interval | # of  | # of Pts. | # of Pts. | # of  | # of Pts. | # of Pts. |
|   | Events | with Events | Observed | Events | with Events | Observed |
|  0 Day - 30 Days | 742 | 367 | 576 | 190 | 119 | 288 |
| 0 Day - 60 Days | 1039 | 426 | 568 | 284 | 155 | 276 |
| 0 Day - 180 Days | 1909 | 509 | 512 | 632 | 204 | 226 |

## Adverse Events

- Adverse Events rates at 6 months after randomization
- For the approach assuming that each lost-to-follow-up patient before the 6-months was event-free
-  		CRT-D group  - 3.21 (1909 events/595 patients)
- 		OPT group -  2.05 (632 events/308 patients)
- For the worst –case (upper limit) approach
-  		CRT-D group  - 3.73 (1909 events/512 patients)
- 		OPT group - 2.80 (632 events/226 patients)

## OPT patients experienced fewer adverse events during the 6 months after randomization 
 Validity of sponsor’s statistical analyses is of concern since: 
Correlation between multi events within a patient was not taking into account
Time of an adverse event occurrence was not taken into account
Many lost-to-follow-up patients were excluded
All exploratory analyses should be interpreted with caution

-  Validity of sponsor’s statistical analyses is of concern since:
- Correlation between multi events within a patient was not taking into account
- Time of an adverse event occurrence was not taken into account
- Many lost-to-follow-up patients were excluded
- All exploratory analyses should be interpreted with caution

- Adverse Events

## Statistical Review Conclusions

- Treatment comparisons for the primary effectiveness and mortality endpoints should be interpreted with caution
- Definition of all-cause hospitalization changed
- Withdrawals not clearly independent of outcome
-  Open label design

## Statistical Review Conclusions

- For the cardiac morbidity and adverse events
- All cardiac morbidity events that occurred outside hospitals were not taken into account
- Lost-to-follow-ups patients, correlation within a patient and times of the events occurrence were not taken into account

## FDA CLINICAL REVIEW of COMPANION 

**Scott E. Proestel, M.D.**
**Medical Officer **
**U.S. Food and Drug Administration**
**July 28, 2004**

## Presentation

**Summarize COMPANION Design**
**Primary Endpoint**
**Secondary Endpoints**
**Additional FDA Efficacy Analyses**
**Safety Analysis**

## COMPANION Summary

**	****Intended to enroll up to 2200 patients with moderate to severe heart failure, and randomize 1:2:2**
**OPT**
**CRT-P**
**CRT-D**

## Inclusion Criteria

**NYHA Class III/IV**
**EF ≤ 35%**
**QRS ****≥**** 120 ms**
**PR > 150 ms**
**LVEDD ****≥**** 60 mm or > 3.0 cm/m****2**
**Optimal medical therapy**

## Inclusion Criteria (cont)

**	****At least one of the following events during previous 12 months:**
**Hospitalization for heart failure**
**Outpatient visit in which IV inotropes or vasoactive infusion were administered for ****≥**** 4 hours**
**ED visit of at least 12 hours duration in which IV HF medications were administered**

## Exclusion Criteria

**Indicated for an ICD**
**Indicated for antibradycardia pacing**
**Expected to receive a heart transplant within 6 months**
**Chronic, medically refractory atrial tachyarrhythmias**
**Unexplained syncope**
**MI within 60 days**

## Exclusion Criteria (cont)

**Unstable angina**
**Uncontrolled HTN**
**CAD with surgical or PCI correction within 60 days**
**Hypertrophic obstructive cardiomyopathy**
**Amyloid disease**
**Hospitalization for heart failure or IV inotropic or vasoactive therapy in excess of 4 hours within 30 days**
**Life expectancy < 6 months due to any other medical conditions**

## Endpoints

**Primary**
**Time to all-cause mortality plus all-cause hospitalization**
**Secondary**
**Total survival**
**Cardiac morbidity**
**Change in maximal oxygen consumption (exercise substudy)**

## Results

**1638 patients enrolled**
**1520 (92.8%) randomized**
**January 2000 - November 2002**
**Enrollment terminated on December 1, 2002**
**(Based on DSMB recommendation)**
**595 CRT-D**
**617 CRT-P**
**308 OPT**

## Baseline Characteristics

|  | CRT-D | CRT-P | OPT |
| --- | --- | --- | --- |
| Age (years) | 65.6 | 65.3 | 66.7 |
| Male | 67.4% | 67.3% | 68.5% |
| Female | 32.6% | 32.7% | 31.5% |
| Class III | 86.1% | 87.0% | 82.1% |
| Class IV | 13.9% | 13.0% | 17.9% |
| Ischemic | 54.6% | 53.7% | 58.8% |
| Non-Ischemic | 45.4% | 46.3% | 41.2% |

## Baseline Characteristics (cont)

|  | CRT-D | CRT-P | OPT
 |
| --- | --- | --- | --- |
| EF | 22.5% | 22.0% | 22.8% |
| LBBB | 72.9% | 69.2% | 69.8% |
| RBBB | 10.3% | 12.3% | 8.8% |
| IVCD | 16.8% | 18.5% | 21.4% |
| QRS | 159 | 159 | 156 |
| PR Interval | 206 | 203 | 202 |

## Pre-Specified Primary Endpoint

**“...****a combination of all-cause mortality and all-cause hospitalization, where all-cause mortality is defined as death from all causes and all-cause hospitalization is defined as admission to a hospital for any reason.”**
**“****In addition, this endpoint will include emergency room visits (or unscheduled office visits) that result in treatment with intravenous (IV) inotropes or vasoactive drugs.”  **

## Primary Endpoint Modifications

**Definition changed 3 times:**
**Hospitalizations > 24 hours**
**Hospitalizations for which the discharge date differed from the admission date**
**Inotrope or vasoactive infusion duration > 4 hours**
**Data to calculate the pre-specified primary endpoint does not exist**

## Ultimate Definition of Primary Endpoint

**All hospitalizations associated with a calendar date change, without regard to whether the hospitalization was considered elective or related to heart failure, with the following exceptions:**
**Index hospitalizations**
**Reimplant attempt hospitalizations**
**Hospitalizations that were considered elective and associated with the device**
**All outpatient infusions of inotropic or vasoactive therapy for > 4 hours for worsening heart failure**
**All-cause mortality**

## Impact of Modifications to thePrimary Endpoint

**Is the new primary endpoint clinically important?**
**Do the changes that occurred in the primary endpoint undermine our belief in the observed effect?**

## FDA Analysis of Mortality(Secondary Endpoint)

|  | CRT-D | CRT-P | OPT |
| --- | --- | --- | --- |
| Total Patients | 595 | 617 | 308 |
| Cumulative Follow-up (yrs) | 777.2 | 812.9 | 374.8 |
| Deaths/100 Pt-Yrs | 13.5 | 16.1 | 20.5 |
| Cardiac Deaths/100 Pt-Yrs | 9.8 | 13.4 | 15.5 |
| Pump Failure Dths/100 Pt-Yrs | 6.7 | 6.5 | 9.1 |
| SCD/100 Pt-Yrs | 2.2 | 5.9 | 4.8 |

## Cardiac Morbidity (Secondary Endpoint)

**Defined as the occurrence of the following events:**
**Worsening heart failure resulting in use of IV vasoactive or inotropic therapy > 4 hours**
**Mechanical respiratory or cardiac support**
**Any cardiac surgery, including heart transplant**
**Resuscitated cardiac arrest or sustained VT requiring intervention**

## Cardiac Morbidity (continued)

**Hospitalization for acute decompensation of heart failure**
**Hospitalization that results in death from cardiac causes**
**Significant device-related events resulting in:**
**Permanent disability**
**Hospitalization for pending death or permanent disability**

## FDA Analysis of Cardiac Morbidity

- 	**However, the definition of a cardiac morbid event ultimately used was any hospitalization during which one or more of the specified “cardiac morbid” events occurred.**
- 	**CRT-D****	****368 cardiac hospitalizations**
**	****	****	****(0.5 events / year)**
**	****OPT****	****312 cardiac hospitalizations**
**	****	****	****(1.0 events / year)**

## Additional Analysesfor Labeling

## CRT-D	2.0 hospitalizations / yearOPT	1.6 hospitalizations / yearCRT-D	11.0 days / yearOPT	10.7 days / year

**FDA Analysis of All-Cause Hospitalization**
**(includes implant hospitalizations)**

## FDA Analysis of Implant Hospitalizations

**Of the 595 CRT-D patients, 541 underwent a successful implant, 47 had unsuccessful attempts, and 7 were intents**
**588 CRT-D patients underwent 641 implant hospitalizations**
**Mean hospitalization was 2.9 +/- 4.9 days**

## FDA Analysis of Safety

**	****FDA reviewed all adverse events, defined in the protocol as undesirable clinical outcomes including device-related events as well as events related to a patient’s general condition.**
**	****CRT-D****	****	****3,732 AEs (4.9 AEs/year)**
**	****OPT ****	****	****1,230 AEs (3.9 AEs/year)**

## FDA Analysis of Safety

**Adverse Events:****	**
**CRT-D****	****14.5% Complications**
**	****	****	****85.5% Observations**
**OPT****	****	****19.6% Complications**
**	****	****	****80.4% Observations**

## Summary

## Summary: Scope of Review

- COMPANION primary and secondary endpoint results
- COMPANION hospitalizations and adverse events
- Consistency with pre-specified clinical and statistical plans
- Presentation of data in device labeling

## Summary: Primary Endpoint

- Modifications were made to the hospitalization definition, part of the primary endpoint, during the course of the COMPANION trial.
- Fundamental statistical assumptions underlying some analyses may not have been met.
- Whether COMPANION demonstrated a benefit for the primary endpoint as originally defined is unknown.
- FDA requests guidance from the panel in interpreting the modified primary endpoint.

## Summary: Mortality

- The CRT-D device was associated with a decrease in all-cause mortality compared to OPT.
- Fundamental statistical assumptions underlying parts of the analysis may not have been met.
- Since the pre-specified statistical plan required consistency between primary and secondary endpoints, FDA requests guidance from the panel in assessing the impact of modifications to the primary endpoint on interpretation of a mortality benefit.

## Summary: Additional Analyses

- The sponsor’s analyses included data obtained from patients after withdrawal.
- When implant hospitalizations were included, the CRT-D device was associated with an increase in all-cause hospitalizations compared to OPT.
- The CRT-D device was associated with an increase in adverse events compared to OPT.
- FDA requests guidance from the panel in determining the how these considerations should impact the sponsor’s CRT-D labeling.