# Presentation: 871240

## Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Alternative Interpretations of the Evidence

- Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Alternative Interpretations of the Evidence

- George A. Diamond, MD;  Sanjay Kaul, MD
- Division of Cardiology
- Cedars-Sinai Medical Center
- Los Angeles, California
*No conflicts to disclose*

## Slide 2

**Notes:**
When my colleague Dr. Sanjay Kaul and I first took note of the meta-analysis by Nissen and Wolski we were struck by the number of zeros in the tabulated data.  

CLICK

We wish to illustrate how this might impact the conclusions under a number of alternative analytic assumptions.

## Rosiglitazone and Cardiovascular Events

-  Rosiglitazone                   Control

- No Event

*Rosiglitazone and Cardiovascular Events*

**       ****27,833 Patients**
**   ****158 Events**
**42 Trials**

*15,470*

*86*

*72*

*12,205*

- MI

- Myocardial Infarction

-    0.59%                    0.55%                 Event Rate*    *

**Notes:**
Here’s the pooled data from all 42 trials with respect to myocardial infarction. 

CLICK

The event rates are very small—well under 1 percent—and the difference between the treatment and control groups is smaller still.  Most of these trials reported no events at all in the treatment or control groups.

## Rosiglitazone and Cardiovascular Events

- Myocardial Infarction

**Notes:**
This slide—which looks something like a three dimensional game of sudoku—breaks up the pooled 2x2 data matrix on the previous slide into 42 separate 2x2 tables (6 across times 7 down) with respect to MI...one for each trial. The number of patients in each cell is represented by the height of the bar.  

The black squares represent the 4 trials that were excluded because no events were observed in BOTH the treatment and control groups—leaving 38 trials for analysis.

Note that most trials were relatively small in size.

## Rosiglitazone and Cardiovascular Events

- Cardiovascular Death

**Notes:**
This is a similar summary of the trials with respect to cardiovascular death. Here, 19 trials were excluded because no events were observed in BOTH groups.

Note the number of holes—the sparsity—of the data.

## Rosiglitazone and Cardiovascular Events

- Peto Meta-Analysis

- Odds Ratio

- 1

**   ****Myocardial Infarction                      Cardiovascular Death**

- 1.43 (1.03-1.98)
- p=0.03
- N=38

- Odds Ratio

- 1.64 (0.98-2.14)
- p=0.06
- N=23

**Notes:**
Here’s the results of the analysis by Nissen and Wolski along with conventional meta-analytic forest plots that were not reported in the NEJM article.

Although the odds ratios are both increased (the one for MI significantly so) the confidence intervals for the individual studies and the meta-analytic result are rather wide.

## Rosiglitazone and Cardiovascular Events

- Myocardial Infarction

**Notes:**
In additon to the excluded trials, a large number of the INCLUDED trials exhibited zero events in one or the other treatment arm.

There were 26 such instances out of the 38 trials analyzed for MI—20 in the control group and 6 in the treatment group...represented here as gold squares...

## Rosiglitazone and Cardiovascular Events

- Cardiovascular Death

**Notes:**
...and 17 such instances out of the 23 trials analyzed for cardiovascular death—15 in the control group and 2 in the treatment group. 

Might all these zeros have affected the analyses?

## Rosiglitazone and Cardiovascular Events

- Impact of Zero Events on Peto’s Odds Ratio

| Zero | Oi-Ei | MI | Death |
| --- | --- | --- | --- |
| Control |  | 20 | 15 |
| Treatment |  | 6 |  2 |

**Notes:**
We can answer this question by inspecting the equation used to calculate Peto’s odds ratio. The term O minus E in the numerator represents the difference between the observed and expected cell counts in the treatment group. The number of zero cells affects the calculation of this term and therefore the resultant odds ratio.

CLICK

The table below the equation shows that zero cell counts in the control group inflate the odds ratio while zero cell counts in the treatment group deflate the odds ratio. Because there were more zeros in the control group—by a ratio of 20:6 for MI and 15:2 for death—the calculation of Peto’s odds ratio was inflated in Nissen and Wolski’s analysis.

## Rosiglitazone and Cardiovascular Events

- Cardiovascular Death

**Notes:**
We can mitigate this problem by applying one or another continuity corrections to the data...effectively filling in the zeros.

## Rosiglitazone and Cardiovascular Events

- Continuity Correction

- Sweeting et al, What to add to nothing? Stat Med 2006;23:1351-75.

**Notes:**
One can apply such corrections by adding some small value—1/2 or something proportional to the sample size—to all cells of a trial exhibiting no events at all, or to trials exhibiting zeros in only one study arm. 

We therefore performed a variety of alternative analyses on the Nissen and Wolski data using different meta-analytic models and different corrections. The technical details are in a manuscript which will be posted online on the Annals of internal Medicine website on August 7.

## Rosiglitazone and Cardiovascular Events

- Meta-Analytic Sensitivity

- Peto ( - )
- Inverse variance 1/N ( - )
- Inverse variance 1/2 ( - )
- Mantel-Haenszel 1/N ( - )
- Mantel-Haenszel 1/2 ( - )
- Mantel-Haenszel 1/N (+)
- Mantel-Haenszel 1/2 (+)
- Uniform Bayes 1/N (+)
- Uniform Bayes 1/2 (+)

**  ****Myocardial Infarction                 Cardiovascular Death**

- Odds Ratio                                    Odds Ratio

- 0.5     1.0     1.5     2.0     2.5     3.0

- 0.5     1.0     1.5     2.0     2.5     3.0

**Notes:**
This slide summarizes our results. A minus sign indicates analyses that excluded the zero event trials. A plus sign indicates analyses that included these trials by applying one of two continuity corrections. 

The point estimates of the odds ratio are represented by the vertical black bars and the 95% confidence intervals are represented by the horizontal colored bars. Statistical significance is indicated if the horizontal bar does not cross the vertical line at unity.

Peto’s model—the one used by Nissen and Wolski--produces the highest values (for both death or MI) and the only statistically significant result (for MI only). These additional analyses emphasize the degree of uncertainty in these assessments.  None establish or exclude the possibility of increased risk.

You need to mention about the different methods we used!

## Rosiglitazone and Cardiovascular Events

- Relative Risk Threshold

- Uncorrected

- Corrected

-   Cardiovascular Death

- Magnitude of Harm

- Relative Risk Threshold

- Uncorrected

- Corrected

-   Myocardial Infarction

- Probability of Harm

**Notes:**
So what does it all mean?

This slide quantifies the cumulative probability of harm—increase in risk—on the y-axis based on the odds ratio distributions on the previous slide as a function of varying risk thresholds along the x-axis.

The yellow curve is for the uncorrected Peto model used by Nissen and Wolski which produced the highest odds ratios and the green curve is for an alternative corrected model. The difference between the curves illustrates the wide range of values that we observed.

For both death and MI, the probability of at least a 10% increase in risk is around 95% for both death and MI using the uncorrected data but in the range of 55% for MI and 40% for death using corrected data. These values are lower than those implied by Nissen and Wolski’s point estimates reporting a 43% increase in MI and a 64% increase in cardiovascular death.

## Rosiglitazone and Cardiovascular Events

- Limitations of the Published Meta-Analysis

-  Not designed to assess outcomes
-  No central adjudication of events
-  No standardized definitions of events
-  Limited sample size
-  Short term duration
-  No patient level data
** ****No sensitivity analysis**
** ****No continuity correction**

**Notes:**
The authors reported a number of limitations involving their analysis and our analyses are subject to the very same limitations. 

However, we have highlighted two additional limitations not considered by them...the sensitivity of their conclusions to alternative meta-analytic assumptions...and the influence of continuity corrections on the quantitative assessment of risk. Although we have not investigated the entire spectrum of these alternative analytic methods,  
our consideration of these factors tempers Nissen and Wolski’s assessment of risk.

At this point, my colleague Dr Sanjay Kaul will summarize the application of these same methods to the analysis of clinically relevant subgroups.

Thank you.

## Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Alternative Interpretations of the Evidence

- Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Alternative Interpretations of the Evidence

- Sanjay Kaul, MD; George A. Diamond, MD
- Division of Cardiology
- Cedars-Sinai Medical Center
- Los Angeles, California
*No conflicts to disclose*

**Notes:**
Use this slide only if we are not presenting in tandem.

## Rosiglitazone and Cardiovascular Events

-  Is there heterogeneity?
- 	- What is the impact of continuity corrections on    	  clinically relevant subgroups?
-  Are the risk estimates consistent with other studies?

*Rosiglitazone and Cardiovascular Events*
- Key Questions Regarding the Published Meta-Analysis

**Notes:**
Of the 3 key questions relating to the Nissen and Wolski meta-analysis, Dr. Diamond addressed the first. The other two (...)  will be the focus of my presentation.

## Rosiglitazone and Cardiovascular Events

-  Cochran’s Q test of heterogeneity		Limited ability to detect variability across studies with 	sparse data (low statistical power)

- Even if studies are statistically homogeneous there may be clinical heterogeneity in study design and population

*Rosiglitazone and Cardiovascular Events*
- Is There Heterogeneity?

**Notes:**
The authors justified pooling the studies on the basis of lack of statistical heterogeneity as assessed by the conventional Cochran’s Q test. 
This test has limited ability to detect variability across studies with sparse data. 

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Clinical Heterogeneity in Patient Populations

**Notes:**
Alternative patient populations such as diabetics and nondiabetics may not be poolable.

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Clinical Heterogeneity in Trial Design

**Notes:**
Alternative trial designs may not be poolable. 
Furthermore, it might not be unreasonable to question whether short–term trials may reliably predict long-term outcomes! 

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Clinical Heterogeneity in Treatment Groups

**Notes:**
Alternative treatment comparator groups may not be poolable!
There were seven treatment comparison strata involving 2 different doses of RSG.

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Is There Heterogeneity?

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Meta-Analytic Subgroups

**Notes:**
Subgroup analyses of uncorrected odds ratio for the risk of MI in small trials combined and the individual data for the two large trials are shown. Although the point estimates are elevated, the CI overlap unity suggesting risk differences are not statistically significant. The overall pooled estimate of the smaller and larger trials combined indicate a statistically significant increase in risk.
Click
Corrected data using the Mantel-Haenszel model with continuity correction lowers the pooled risk estimates such that the overall pooled estimate is now no longer statistically significant! 

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Meta-Analytic Subgroups

**Notes:**
Similar observations are made with the analysis of CV death.
The corrected pooled estimates are lower with CI overlapping unity!

## Rosiglitazone and Cardiovascular Events

*Rosiglitazone and Cardiovascular Events*
- Meta-Analytic Subgroups

**Notes:**
The subgroup analysis for uncorrected data and corrected data are shown with regards to subgroup of patients with and without diabetes and different treatment comparison groups. The point estimates of corrected analyses were consistently lower than the uncorrected analyses. None of the subgroups showed increased risks that were statistically significant. 

## Rosiglitazone and Cardiovascular Events

- Meta-Analytic Subgroups

- Cardiovascular Death

**Notes:**
Similar observations are made with the subgroup analysis for CV death with regards to uncorrected as well as corrected analyses. 
None of these analyses conclusively adjudicate the association between rosiglitazone and the risk for myocardial infarction or cardiovascular death in particular subgroups of patients.

## Rosiglitazone and Cardiovascular Events

- 0

- 1

- 2

- 3

- RECORD (N=4407)

**Rate ratio**

- Balanced Cohort Study
-  (N=33363)

- Myocardial Infarction/Ischemia

- GSK ICT analysis
- (N=42 trials)

- Cochrane Review (N=18 trials)

*Rosiglitazone and Cardiovascular Events*
- Are the Risk Estimates Consistent?

- Nonsignificantly increased odds ratio

**Notes:**
Several additional analyses have assessed cardiovascular risk associated with RSG. 
The Integrated Clinical Trial Analyses conducted by the sponsor included nearly 30 of the 42 trials included in the Nissen and Wolski meta-analysis. 
An Exact Logistic Regression Model was used for pooling the data, thereby excluding the zero total event trials as in the Peto method. 
The results indicate a 30% statistically significant increase in the risk of all MYOCARDIAL ISCHEMIC events with RSG. 
In light of the alternative analyses that we have just shown you, what might be their impact on these results?

An interim analysis of the RECORD trial (that had the largest number of MI events) revealed insufficient data to determine if there was an increase in MI, probably due to low power related to unexpectedly low event rates and incomplete follow-up.

A large observational study, the Balanced Cohort Study, commissioned by the sponsor, showed no significant differences in risk of MI between RSG and comparator groups.

A recently published Cochrane Review of 18 studies amongst patients with diabetes found a tendency towards increased risk of MI with RSG, but the differences were not reported to be statistically significant.

Thus, the risk for myocardial infarction for diabetic patients taking rosiglitazone is uncertain: neither increased nor decreased risk is established.

## Rosiglitazone and Cardiovascular Events

-  Sensitive to continuity correction
-  Sensitive to subgroup analysis
-  If present, magnitude of harm is small

- We need more data!

*Rosiglitazone and Cardiovascular Events*
- Conclusions

**Notes:**
In conclusion, the risk estimates are.......
Click
Clearly more data are needed to adjudicate the UNCERTAIN association between RSG and cardiovascular risk!
We believe that only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety.

Concurrently, meta-analytic approaches for assessment of sparse data (especially safety) should be refined and standardized. 

Finally, we need to be aware of the limitations of meta-analyses and maintain a healthy skepticism about its reproducibility and applicability.

## Slide 28