![](media/image1.png)**DIVISION OF CARDIO-RENAL DRUG PRODUCTS**

***Joint Clinical Review***

**NDA**: 20-297

**Sponsor**: Glaxo SmithKline

**Submission**: SE8-009 (27 September 2002): supplement requesting an
indication for use of carvedilol in patients with left ventricular
dysfunction after myocardial infarction.

**Review date**: December 30, 2002

**Reviewers**: N. Stockbridge, M.D., Ph.D., HFD-110

H.M. James Hung, Ph.D., HFD-710

**Concurrence**: G. Chi, Ph.D., HFD-710

**Summary:**

**Distribution**: NDA 20-297

HFD-110/Project Manager

HFD-710/Hung

HFD-110/Stockbridge

HFD-700/Anello

HFD-710/Chi

Table of contents

*1 CAPRICORN [3](#capricorn)*

1.1 Study title [3](#study-title)

1.2 Sources [3](#sources)

1.3 Design [3](#design)

1.3.1 Population [3](#population)

1.3.2 Procedures [3](#procedures)

1.3.3 End points [4](#end-points)

1.3.4 Administration [4](#administration)

1.3.5 Amendments [4](#amendments)

1.4 Conduct [4](#conduct)

1.5 Results [5](#results)

1.5.1 Baseline characteristics [5](#baseline-characteristics)

1.5.2 Withdrawals [5](#withdrawals)

1.5.3 Concomitant medication [6](#concomitant-medication)

1.5.4 Primary end points [6](#primary-end-points)

1.5.5 Secondary end points [10](#secondary-end-points)

1.5.6 Other analyses [10](#other-analyses)

1.5.7 Safety [14](#safety)

2 CHAPS [15](#chaps)

2.1 Study title [15](#study-title-1)

2.2 Sources [15](#sources-1)

2.3 Design [15](#design-1)

2.3.1 Population [15](#population-1)

2.3.2 Procedures [15](#procedures-1)

2.3.3 End points [15](#end-points-1)

2.3.4 Administration [16](#administration-1)

2.3.5 Amendments [16](#amendments-1)

2.4 Conduct [16](#conduct-1)

2.5 Results [17](#results-1)

2.5.1 Baseline characteristics [17](#baseline-characteristics-1)

2.5.2 Concomitant medications [17](#concomitant-medications)

2.5.3 Primary end points [18](#primary-end-points-1)

2.5.4 Secondary end points [18](#secondary-end-points-1)

2.5.5 Other analyses [19](#other-analyses-1)

2.5.6 Safety [19](#safety-1)

3 Conclusions [20](#conclusions)

**List of Tables**

Table 1. Baseline characteristics (CAPRICORN)
[5](#__RefHeading___Toc26746874)

Table 2. Reasons for discontinuation (CAPRICORN)
[5](#__RefHeading___Toc26746875)

Table 3. Primary end points (CAPRICORN) [6](#__RefHeading___Toc26746876)

Table 4. Primary end points (CAPRICORN) [7](#__RefHeading___Toc26746877)

Table 5. 95% confidence limits for subgroups (CAPRICORN)
[8](#__RefHeading___Toc26746878)

Table 6. Time to hospitalization for heart failure (CAPRICORN)
[10](#__RefHeading___Toc26746879)

Table 7. Adjudicated cause of death (CAPRICORN)
[10](#__RefHeading___Toc26746880)

Table 8. Adjudicated cause of death or cardiovascular hospitalization
(CAPRICORN) [11](#__RefHeading___Toc26746881)

Table 9. Causes for all hospitalizations (CAPRICORN)
[11](#__RefHeading___Toc26746882)

Table 10. Time to event for death or cardiovascular hospitalization
(CAPRICORN) [12](#__RefHeading___Toc26746883)

Table 11. Change in heart rate by mortality status and treatment group
(CAPRICORN) [14](#__RefHeading___Toc26746884)

Table 12. Common adverse events (CAPRICORN)
[14](#__RefHeading___Toc26746885)

Table 13. Disposition of subjects (CHAPS)
[16](#__RefHeading___Toc26746886)

Table 14. Primary end point events (CHAPS)
[18](#__RefHeading___Toc26746887)

List of Figures

Figure 1. Primary end points (CAPRICORN)
[7](#__RefHeading___Toc26746864)

Figure 2. Hazard ratios for pre-specified subgroups (CAPRICORN).
[9](#__RefHeading___Toc26746865)

Figure 3. Log(-log(survival) vs. log(days) (CAPRICORN)
[9](#__RefHeading___Toc26746866)

Figure 4. Secondary end points (CAPRICORN)
[10](#__RefHeading___Toc26746867)

Figure 5. Hazard ratio for mortality by country (CAPRICORN)
[11](#__RefHeading___Toc26746868)

Figure 6. Hazard ratio for mortality by center (CAPRICORN)
[12](#__RefHeading___Toc26746869)

Figure 7. Vital signs (CAPRICORN) [13](#__RefHeading___Toc26746870)

Figure 8. Distribution of changes in heart rate (CAPRICORN)
[14](#__RefHeading___Toc26746871)

Figure 9. Disposition of subjects (CHAPS)
[17](#__RefHeading___Toc26746872)

Figure 10. Primary end point (CHAPS) [18](#__RefHeading___Toc26746873)

# CAPRICORN

## Study title

SB-105517/RSD-101T91/1/Study 269: Effect of carvedilol in patients with
left ventricular dysfunction following an acute myocardial infarction
(CAPRICORN), entitled elsewhere as \"A multi-national, multi-centre,
randomised, double-blind, parallel group study to determine the effects
of carvedilol on mortality and morbidity in patients with left
ventricular dysfunction, with or without clinical evidence of heart
failure, post myocardial infarction\".

## Sources

The description of the study design is from the fully amended protocol,
dated 27 July 1999. There are noted to be 4 protocol amendments (03 July
1997, 22 December 1997, 22 April 1998, and 27 July 1999) and one
\"modification\" (8 August 1997).

The final study report is an undated manuscript; the PDF file is dated
27 September 2002. There is also a statistical report dated 20 September
2002, and there are datasets with supporting documentation.

A set of amendments was not provided. The protocol does not make clear
what changes were made by any amendment.

## Design

### Population

Subjects were to be over age 18, with a myocardial infarction within 21
days, and left ventricular dysfunction.

Myocardial infarction required two of the following (1) ischemic chest
pain lasting \>20 minutes or pulmonary edema, (2) pathological Q wave or
ST elevation and T wave inversion on adjacent leads, and (3) cardiac
enzymes or isozymes \> twice upper limit of normal.

Left ventricular dysfunction was diagnosed by LVEF \<40% by 2D echo,
radionuclide, or contrast angiography, or a wall motion index \<1.3.

Subjects without contraindication or demonstrated intolerance were to be
on an ACE inhibitor for at least 48 hours, with the dose stable for at
least 24 hours.

Exclusions were (1) need for intravenous inotropes, (2) receipt of
beta-blocker after the index myocardial infarction, (3) unstable angina,
(4) obstructive or regurgitative valvulopathy or hypertrophic
cardiomyopathy, (5) uncontrolled ventricular arrhythmias, (6) sick sinus
syndrome or second or third degree heart block without a pacemaker, (7)
blood pressure outside 90-160/\<95 mmHg or heart rate \<60 bpm, (8) COPD
or bronchospastic disease, (9) disease impairing absorption or
metabolism, (10) unstable insulin-dependent diabetes, (11) pregnancy or
lactation, (12) other life-threatening disease, (13) sensitivity to
alpha or beta blockers, (14) need for MAO inhibitors, calcium channel
blockers other than long-acting dihydropyridines, alpha blockers,
labetelol, beta blockers, or beta agonists.

### Procedures

In blinded fashion, qualified subjects were to be randomized, using
randomly permuted blocks, to placebo or carvedilol 6.25 mg bid. Study
drug was then to be down-titrated if necessary, and up-titrated, as
tolerated, to 12.5 mg bid at 3 to 10 days, and then again to 25 mg bid
at 5-10 days. Advice was to avoid reducing the dose of ACE inhibitor by
offsetting the times of dosing; if ACE inhibitor dose was reduced,
investigators were to attempt to restore the dose.

After the dose of study drug was stabilized, visits were every 3 months.
Subjects were followed until the end of the study, until 633 primary end
point events had occurred.

At the end of the study, the dose of study drug was to be reduced in
steps over a 2-week period.

### End points

The primary analysis was to be based on all randomized subjects. There
were two primary end points. All-cause mortality plus cardiovascular
hospitalizations was to be evaluated using a two-sided logrank test with
an alpha-level of 0.045. All-cause mortality was to be analyzed with a
two-sided logrank test with an alpha-level of 0.005.

There was a planned interim analysis for mortality at 125 deaths, to be
evaluated with alpha-level of 0.001, leaving the final analysis of
mortality with alpha-level of 0.004.

Hazard ratios and 95% confidence limits were to be based on the Cox
Proportional Hazard models with covariates of treatment group and a long
list of risk factors \"as appropriate\". Graphical display was to be by
Kaplan-Meier life table.

The sample size was originally estimated at 2600; this was adjusted to
1850.

Secondary end points were time to sudden death and time to first
hospitalization for heart failure.

### Administration

There was an executive steering committee charged with the overall
conduct, including sub-studies.

There was a data safety monitoring board, which saw blinded data.

There was an end point adjudication committee to decide which deaths
were cardiovascular, and which hospitalizations were cardiovascular or
for heart failure.

### Amendments

Originally, the sole primary end point was all-cause mortality and
mortality plus cardiovascular hospitalization was a secondary end point.
On the basis of events outside of CAPRICORN, in March 1999, the DSMB
recommended that subjects who developed heart failure be permitted
open-label beta blocker. Because this was likely to reduce the overall
mortality effect, the DSMB is said to have recommended an unspecified
change in the primary end point to enhance the study\'s power. As a
result, the protocol was amended 27 July 1999 and this change was
submitted to FDA on 16 August 1999[^1]. This amendment allowed subjects
with heart failure to discontinue randomized treatment and start
open-label beta-blocker. It also called for the establishment of a
co-primary end point. The number of end point events was left as 633;
since the combined event rate would be higher, the expected total
enrollment fell from 2600 to 1850. The protocol-specified interim
analysis occurred after this amendment.

## Conduct

Enrollment for CAPRICORN was from 23 June 1997 to 3 February 2000.

A total of 1949 subjects were randomized at 163 centers in Russia (600),
Spain (333), United Kingdom (230), Hungary (139), Israel (118),
Lithuania (98), Australia (96), New Zealand (95), United States (83),
Germany (45), France (35), Italy (31), Belgium (21), Netherlands (14),
Canada (5), Luxembourg (3), and Ireland (3). This total does not include
10 subjects who never received their assigned treatments, but were
included in the sponsor\'s intent-to-treat analyses. Individual sites
enrolled 1 (24 sites) to 153 subjects. Five of the 6 highest enrolling
centers were in Russia.

Twelve subjects in the placebo group received carvedilol as incorrectly
dispensed study drug for some unspecified period. Among them, there were
1 death and 3 cardiovascular hospitalizations. Eighteen subjects in the
carvedilol group received placebo incorrectly for some unspecified
period. Among them, there were 2 deaths and 5 cardiovascular
hospitalizations.

Eighteen subjects were unblinded before having end point events. Of
these, 3 on placebo and 3 on carvedilol later had end point events.

## Results

### Baseline characteristics

As might be expected for a study of this size, the baseline
characteristics of the two groups were similar, as shown in Table 1.

[]{#__RefHeading___Toc26746874 .anchor}Table 1. Baseline characteristics
(CAPRICORN)[^2]

+-----------------+-------+--------+-----------------+-------+--------+
|                 | Pl    | Carv   |                 | Pl    | Carv   |
|                 | acebo | edilol |                 | acebo | edilol |
|                 |       |        |                 |       |        |
|                 | N=984 | N=975  |                 | N=984 | N=975  |
+=================+=======+========+=================+=======+========+
| Age             | 63    | 63     | Use at          | 97    | 98     |
|                 |       |        | randomization   |       |        |
|                 |       |        |                 | 35    | 33     |
|                 |       |        | ACE inhibitor   |       |        |
|                 |       |        | (%)             | 85    | 85     |
|                 |       |        |                 |       |        |
|                 |       |        | Beta-blocker    | 24    | 22     |
|                 |       |        | (%)             |       |        |
|                 |       |        |                 | 21    | 20     |
|                 |       |        | Aspirin (%)     |       |        |
|                 |       |        |                 |       |        |
|                 |       |        | Lipid lowering  |       |        |
|                 |       |        | (%)             |       |        |
|                 |       |        |                 |       |        |
|                 |       |        | Heparin (%)     |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
| Sex (% male)    | 74    | 73     |                 |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
| Index MI:       | 55    | 59     |                 |       |        |
|                 |       |        |                 |       |        |
| Anterior MI (%) | 94    | 95     |                 |       |        |
|                 |       |        |                 |       |        |
| Cardiac pain    | 18    | 19     |                 |       |        |
| (%)             |       |        |                 |       |        |
|                 | 85    | 84     |                 |       |        |
| Pulm edema (%)  |       |        |                 |       |        |
|                 | 10    | 11     |                 |       |        |
| ↑ cardiac enz   |       |        |                 |       |        |
| (%)             | 32    | 31     |                 |       |        |
|                 |       |        |                 |       |        |
| IV beta blocker | 73    | 73     |                 |       |        |
| (%)             |       |        |                 |       |        |
|                 | 65    | 63     |                 |       |        |
| Oral beta       |       |        |                 |       |        |
| blocker (%)     | 37    | 36     |                 |       |        |
|                 |       |        |                 |       |        |
| IV nitrate (%)  | 13    | 12     |                 |       |        |
|                 |       |        |                 |       |        |
| IV heparin (%)  |       |        |                 |       |        |
|                 |       |        |                 |       |        |
| Thrombolytic    |       |        |                 |       |        |
| (%)             |       |        |                 |       |        |
|                 |       |        |                 |       |        |
| Angioplasty (%) |       |        |                 |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        |                 |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        |                 |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        |                 |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        | CHF at entry    | 47    | 48     |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        | Systolic BP     | 121   | 122    |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        | Heart rate      | 77    | 77     |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        | LVEF (%)        | 33    | 33     |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        | Index MI to     | 10    | 10     |
|                 |       |        | random (d)      |       |        |
+-----------------+-------+--------+-----------------+-------+--------+
|                 |       |        | MI prior to     | 29    | 31     |
|                 |       |        | index (%)       |       |        |
+-----------------+-------+--------+-----------------+-------+--------+

### Withdrawals

By the sponsor\'s count, 468 subjects discontinued treatment (231 on
placebo and 237 on carvedilol). Reasons for discontinuation were not
described. By the reviewers\' analysis of the WDRAW dataset, there were
501 withdrawals (247 on placebo and 254 on carvedilol). Reasons for
withdrawal were as shown in Table 2.

[]{#__RefHeading___Toc26746875 .anchor}Table 2. Reasons for
discontinuation (CAPRICORN)

+----------------------------------+---------------+-------------------+
|                                  | Placebo       | Carvedilol        |
|                                  |               |                   |
|                                  | N=984         | N=975             |
+==================================+===============+===================+
| Adverse events                   | 134           | 153               |
+----------------------------------+---------------+-------------------+
| Protocol deviation               | 28            | 30                |
+----------------------------------+---------------+-------------------+
| Inadequate response              | 24            | 8                 |
+----------------------------------+---------------+-------------------+
| Loss to follow-up                | 9             | 10                |
+----------------------------------+---------------+-------------------+
| Other                            | 52            | 53                |
+----------------------------------+---------------+-------------------+

However, the \"Other\" category includes some reasons that could
reasonably have been categorized otherwise.

By the sponsor\'s count, there were only 2 subjects on placebo and 4 on
carvedilol for whom complete ascertainment of mortality and
cardiovascular hospitalization are missing. It is not clear how to
resolve this claim with 19 subjects said to be lost to follow-up in the
WDRAW dataset.

### Concomitant medication

During the study, by the sponsor\'s analysis open-label beta-blockers
were taken by 145 subjects in the placebo group and 91 subjects on
carvedilol. By the reviewers\' count, there were 135 subjects on placebo
and 133 on carvedilol who received open-label beta blockers[^3].

The reviewers\' analysis showed that use of ACE inhibitors or
angiotensin receptor antagonists was similar on placebo (n=589) and
carvedilol (n=558)[^4].

Neither the sponsor nor the reviewers performed a thorough review of
other concomitant medications.

### Primary end points

The sponsor\'s analyses of the primary end points are shown in Table 3.

[]{#__RefHeading___Toc26746876 .anchor}Table 3. Primary end points
(CAPRICORN)[^5]

+--------------+----------+-----------+-------------+-------+--------+
|              | Events   |           | Hazard      | P     | Alpha  |
|              |          |           |             | value |        |
|              |          |           | ratio       |       |        |
|              |          |           |             |       |        |
|              |          |           | (95% CI)    |       |        |
+==============+==========+===========+=============+=======+========+
|              | Placebo  | C         |             |       |        |
|              |          | arvedilol |             |       |        |
|              | N=984    |           |             |       |        |
|              |          | N=975     |             |       |        |
+--------------+----------+-----------+-------------+-------+--------+
| Death or CV  | 367      | 340       | 0.92        | 0.297 | 0.045  |
| hos          |          |           |             |       |        |
| pitalization |          |           | (0.80-1.07) |       |        |
+--------------+----------+-----------+-------------+-------+--------+
| Death        | 151      | 116       | 0.77        | 0.031 | 0.004  |
|              |          |           |             |       |        |
|              |          |           | (0.60-0.98) |       |        |
+--------------+----------+-----------+-------------+-------+--------+

The life table analyses are shown in Figure 1.

  ---------------------------------------------------- ---------------------------------------------------
  ![](media/image2.png){width="3.0118055555555556in"   ![](media/image3.png){width="3.220138888888889in"
  height="2.3673611111111112in"}                       height="2.3673611111111112in"}

  ---------------------------------------------------- ---------------------------------------------------

[]{#__RefHeading___Toc26746864 .anchor}Figure 1. Primary end points
(CAPRICORN)

Sponsor\'s analyses of mortality plus cardiovascular hospitalization
(LEFT) and mortality alone (RIGHT).

The reviewers\' analyses of the primary end points excluded the 10
subjects who never received treatment. The results are shown in Table 4.

[]{#__RefHeading___Toc26746877 .anchor}Table 4. Primary end points
(CAPRICORN)[^6]

+--------------+----------+-----------+-------------+-------+--------+
|              | Events   |           | Hazard      | P     | Alpha  |
|              |          |           |             | value |        |
|              |          |           | Ratio       |       |        |
|              |          |           |             |       |        |
|              |          |           | (95% CI)    |       |        |
+==============+==========+===========+=============+=======+========+
|              | Placebo  | C         |             |       |        |
|              |          | arvedilol |             |       |        |
|              | N=984    |           |             |       |        |
|              |          | N=975     |             |       |        |
+--------------+----------+-----------+-------------+-------+--------+
| Death or CV  | 366      | 337       | 0.92        | 0.271 | 0.045  |
| hos          |          |           |             |       |        |
| pitalization |          |           | (0.79,      |       |        |
|              |          |           | 1.07)       |       |        |
+--------------+----------+-----------+-------------+-------+--------+
| Death        | 150      | 115       | 0.77        | 0.032 | 0.004  |
|              |          |           |             |       |        |
|              |          |           | (0.60,      |       |        |
|              |          |           | 0.98)       |       |        |
+--------------+----------+-----------+-------------+-------+--------+

These results are nearly identical to the sponsor\'s analyses.

The sponsor\'s subgroup analyses of the primary end points are
summarized in Table 5.

[]{#__RefHeading___Toc26746878 .anchor}Table 5. 95% confidence limits
for subgroups (CAPRICORN)

  ------------------------------------------------------------------------
                      Subgroup (N)          Death+ CV hosp  Death
  ------------------- --------------------- --------------- --------------
  Age                 \<70 (1341)           0.77-1.12       0.56-1.10

                      \>70 (618)            0.74-1.18       0.55-1.10

  Sex                 Male (1440)           0.81-1.15       0.58-1.06

                      Female (519)          0.63-1.08       0.49-1.09

  Country             Russia (600)          0.56-1.01       0.55-1.31

                      Other (1359)          0.84-1.18       0.55-0.98

  Earlier MI          Yes (589)             0.78-1.24       0.62-1.22

                      No (1370)             0.72-1.05       0.45-0.91

  Site of MI          Anterior (1108)       0.80-1.19       0.51-0.97

                      Inferior (410)        0.74-1.45       0.82-2.27

                      Other (441)           0.57-1.03       0.30-0.90

  Thrombolytic        Yes (718)             0.70-1.17       0.43-1.12

                      No (1241)             0.78-1.12       0.59-1.04

  Angioplasty         Yes (243)             0.73-1.69       0.36-1.62

                      No (1716)             0.77-1.05       0.58-0.99

  Diuretic            Yes (658)             0.70-1.11       0.49-0.96

                      No (1301)             0.77-1.13       0.59-1.17

  Heart failure       Yes (936)             0.72-1.07       0.59-1.08

                      No (1023)             0.77-1.21       0.47-1.03

  Angina              Yes (1090)            0.76-1.12       0.52-0.95

                      No (869)              0.72-1.15       0.58-1.28

  Hypertension        Yes (1055)            0.75-1.11       0.61-1.14

                      No (904)              0.73-1.15       0.44-0.95

  Diabetes            Yes (437)             0.80-1.13       0.61-1.44

                      No (1522)             0.66-1.16       0.53-0.96

  Systolic BP         \<110 (453)           0.76-1.41       0.52-1.40

                      110-130 (1039)        0.77-1.16       0.55-1.08

                      \>130 (464)           0.57-1.06       0.42-1.11

  Killip class        Class I (1289)        0.79-1.15       0.60-1.18

                      Class II (593)        0.65-1.09       0.46-0.98

                      Class III (65)        0.97-3.84       0.70-3.95
  ------------------------------------------------------------------------

The sponsor\'s point estimates for the hazard ratios for mortality from
these pre-specified subgroups are shown in Figure 2.

  -----------------------------------------------------------------------
  ![](media/image4.wmf)

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746865 .anchor}Figure 2. Hazard ratios for
pre-specified subgroups (CAPRICORN).

Reviewers\' plot of sponsor\'s analyses. Data points represent hazard
ratio for mortality plotted as a function of the total number of
subjects enrolled in the subgroup. Horizontal dashed line is the overall
estimated treatment effect. Dotted envelope is calculated based on the
overall 50% and 95% confidence limits scaled for the observed range of
sample sizes.

  -----------------------------------------------------------------------
  ![](media/image5.wmf)

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746866 .anchor}Figure 3. Log(-log(survival) vs.
log(days) (CAPRICORN)

Reviewers\' analysis. A parallel time course is indicative of a constant
hazard ratio.

As shown in Figure 3, log(-log(survival) vs. log(time) curves are
approximately parallel and straight, indicating that the hazard ratio
seems to be constant over time.

### Secondary end points

Time to sudden death does not appear to have been analyzed by the
sponsor. As part of this review, time to sudden death was analyzed and
had a log-rank p-value of 0.120.

Time to hospitalization for CHF was compared as shown in Table 6.

[]{#__RefHeading___Toc26746879 .anchor}Table 6. Time to hospitalization
for heart failure (CAPRICORN)[^7]

+-----------------+-----------+-------------+---------------+--------+
|                 | Events    |             | Hazard        | P      |
|                 |           |             |               | value  |
|                 |           |             | Ratio         |        |
|                 |           |             |               |        |
|                 |           |             | (95% CI)      |        |
+=================+===========+=============+===============+========+
|                 | Placebo   | Carvedilol  |               |        |
|                 |           |             |               |        |
|                 | N=984     | N=975       |               |        |
+-----------------+-----------+-------------+---------------+--------+
| CHF             | 138       | 118         | 0.86          | 0.216  |
| hospitalization |           |             |               |        |
|                 |           |             | (0.67-1.09)   |        |
+-----------------+-----------+-------------+---------------+--------+

Life table analyses of the secondary end points are shown in Figure 4.

  ---------------------------------- ------------------------------------
  ![](media/image6.wmf)Time to       ![](media/image7.wmf)Time to
  sudden death                       hospitalization for heart failure

  ---------------------------------- ------------------------------------

[]{#__RefHeading___Toc26746867 .anchor}Figure 4. Secondary end points
(CAPRICORN)

Reviewers\' analyses of time to sudden death (LEFT) and time to
hospitalization for heart failure (RIGHT). Curves in red are carvedilol;
curves in green are placebo. The reviewers\' analysis of time to first
hospitalization for heart failure is based upon the 267 subjects with
adjudicated events as indicated in the HF dataset. The log-rank p-value
is 0.320.

### Other analyses

The end point adjudication committee blindly classified causes of death,
as shown in Table 7.

[]{#__RefHeading___Toc26746880 .anchor}Table 7. Adjudicated cause of
death (CAPRICORN)[^8]

+--------------+--------+----------+------------+--------+----------+
|              | P      | Ca       |            | P      | Ca       |
|              | lacebo | rvedilol |            | lacebo | rvedilol |
|              |        |          |            |        |          |
|              | N=984  | N=975    |            | N=984  | N=975    |
+==============+========+==========+============+========+==========+
| Sudden       | 69     | 51       | Presumed   | 12     | 8        |
|              |        |          | CV         |        |          |
+--------------+--------+----------+------------+--------+----------+
| Worsening    | 30     | 18       | CV         | 5      | 8        |
| CHF          |        |          | procedure  |        |          |
+--------------+--------+----------+------------+--------+----------+
| Recurrent MI | 16     | 12       | Stroke     | 5      | 6        |
+--------------+--------+----------+------------+--------+----------+
| Non-CV       | 12     | 12       | Other CV   | 2      | 1        |
+--------------+--------+----------+------------+--------+----------+

Most of the deaths (63%) were sudden or attributed to worsening heart
failure, but, even so, these categories accounted for a disproportionate
amount of the difference between the groups.

The end point adjudication committee also blindly classified causes of
death or cardiovascular hospitalization, as shown in Table 8.

[]{#__RefHeading___Toc26746881 .anchor}Table 8. Adjudicated cause of
death or cardiovascular hospitalization (CAPRICORN)[^9]

+--------------+--------+----------+---------------+--------+---------+
|              | P      | Ca       |               | P      | Car     |
|              | lacebo | rvedilol |               | lacebo | vedilol |
|              |        |          |               |        |         |
|              | N=984  | N=975    |               | N=984  | N=975   |
+==============+========+==========+===============+========+=========+
| Death        | 78     | 65       | Unstable      | 37     | 40      |
|              |        |          | angina        |        |         |
+--------------+--------+----------+---------------+--------+---------+
| Worsening    | 102    | 97       | Nonfatal MI   | 45     | 27      |
| CHF          |        |          |               |        |         |
+--------------+--------+----------+---------------+--------+---------+
| Angina       | 42     | 57       | Stroke/TIA    | 12     | 12      |
+--------------+--------+----------+---------------+--------+---------+
| Other CV     | 51     | 42       |               |        |         |
+--------------+--------+----------+---------------+--------+---------+

Overall hospitalizationsnot just the first and not just
cardiovascularare summarized in Table 9.

[]{#__RefHeading___Toc26746882 .anchor}Table 9. Causes for all
hospitalizations (CAPRICORN)

+--------------+--------+---------+--------------+--------+----------+
|              | P      | Car     |              | P      | Ca       |
|              | lacebo | vedilol |              | lacebo | rvedilol |
|              |        |         |              |        |          |
|              | N=984  | N=975   |              | N=984  | N=975    |
+==============+========+=========+==============+========+==========+
| Any          | 693    | 621     | Other CV     | 70     | 79       |
+--------------+--------+---------+--------------+--------+----------+
| Worsening    | 181    | 151     | Unstable     | 53     | 56       |
| CHF          |        |         | angina       |        |          |
+--------------+--------+---------+--------------+--------+----------+
| Non-CV       | 123    | 96      | MI           | 60     | 37       |
+--------------+--------+---------+--------------+--------+----------+
| CV procedure | 93     | 84      | Stroke, TIA  | 18     | 17       |
+--------------+--------+---------+--------------+--------+----------+
| Angina       | 84     | 92      |              |        |          |
+--------------+--------+---------+--------------+--------+----------+

As part of this review, the reviewers calculated effects on mortality by
country, as shown in Figure 5.

  -----------------------------------------------------------------------
  ![](media/image8.wmf)

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746868 .anchor}Figure 5. Hazard ratio for
mortality by country (CAPRICORN)

Reviewers\' analysis. Data points represent hazard ratio for mortality
plotted as a function of the total number of events. Dotted envelopes
are calculated based on the overall 50% and 95% confidence limits scaled
for the observed range of sample sizes.

Only countries with at least one fatality in each treatment group are
represented in the figure. No countries appear to be outliers in this
analysis.

A similar analysis for the 38 centers with at least one death on placebo
and carvedilol is shown in Figure 6.

  -----------------------------------------------------------------------
  ![](media/image9.wmf)

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746869 .anchor}Figure 6. Hazard ratio for
mortality by center (CAPRICORN)

Reviewers\' analysis. Data points represent hazard ratio for mortality
plotted as a function of the total number of events. Dotted envelopes
are calculated based on the overall 50% and 95% confidence limits scaled
for the observed range of sample sizes.

As part of this review, the time to event was explored for subjects who
had cardiovascular hospitalization but survived, subjects who died
without cardiovascular hospitalization, and subjects who died after
cardiovascular hospitalization. These results are shown in Table 10.

[]{#__RefHeading___Toc26746883 .anchor}Table 10. Time to event for death
or cardiovascular hospitalization (CAPRICORN)[^10]

+------------+-------+---------+-------+----------+-------+---------+
| Time       | CV    |         | Death |          | Death |         |
| (days)     | hosp  |         | only  |          | after |         |
|            | only  |         |       |          | hosp  |         |
+============+=======+=========+=======+==========+=======+=========+
|            | Pl    | Car     | Pl    | Ca       | Pl    | Car     |
|            | acebo | vedilol | acebo | rvedilol | acebo | vedilol |
|            |       |         |       |          |       |         |
|            | N=216 | N=224   | N=83  | N=66     | N=68  | N=50    |
+------------+-------+---------+-------+----------+-------+---------+
| Rand to    | 163   | 145     | ---   | ---      | 136   | 96      |
| hosp       |       |         |       |          |       |         |
|            | 98    | 81      |       |          | 67    | 53      |
| Mean       |       |         |       |          |       |         |
|            |       |         |       |          |       |         |
| Median     |       |         |       |          |       |         |
+------------+-------+---------+-------+----------+-------+---------+
| Rand to    | ---   | ---     | 181   | 193      | 289   | 227     |
| death      |       |         |       |          |       |         |
|            |       |         | 138   | 88       | 272   | 188     |
| Mean       |       |         |       |          |       |         |
|            |       |         |       |          |       |         |
| Median     |       |         |       |          |       |         |
+------------+-------+---------+-------+----------+-------+---------+
| Hosp to    | ---   | ---     | ---   | ---      | 153   | 131     |
| death      |       |         |       |          |       |         |
|            |       |         |       |          | 75    | 49      |
| Mean       |       |         |       |          |       |         |
|            |       |         |       |          |       |         |
| Median     |       |         |       |          |       |         |
+------------+-------+---------+-------+----------+-------+---------+

One would expect that time to death would be longer for the group with
fewer deaths and, perhaps, that time to cardiovascular hospitalization
would be increased in the group with fewer deaths, too. However, these
expectations are not met. The numbers of subjects who died with or
without cardiovascular hospitalization were smaller on carvedilol, but
the time to cardiovascular hospitalization tended to be longer on
placebo, regardless of mortal outcome. Among subjects who died, the
*mean* time to death was longer on carvedilol for subjects without
antecedent cardiovascular hospitalization, but longer on placebo for
subjects with such a hospitalization. The time from hospitalization to
death was also longer on placebo. The *median* time to death was longer
on placebo, among subjects who died, regardless of cardiovascular
hospitalization. Thus, there are some *internal* inconsistencies.

By the sponsor\'s analyses, vital signs differed between the treatment
groups throughout the study. Heart rate was 7 bpm lower on carvedilol
and blood pressure was 3.6/3.0 mmHg lower on carvedilol. All differences
were highly statistically significant by the sponsor\'s analyses.

Vital signs are shown graphically in Figure 7.

  -----------------------------------------------------------------------
  ![](media/image10.wmf)

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746870 .anchor}Figure 7. Vital signs (CAPRICORN)

Reviewers\' analyses. Curves were drawn from LOESS fits to all
observations.

Heart rate effect by mortality status and treatment group is shown in
Table 11 and Figure 8.

[]{#__RefHeading___Toc26746884 .anchor}Table 11. Change in heart rate by
mortality status and treatment group (CAPRICORN)[^11]

  ------------------------------------------------------------------------------------------------------------------
          Placebo                                 Carvedilol                                                  
  ------- --------- ------ -------- ------ ------ ------------ ------ ------ ---- -------- ------ ----- ----- ------
          N         Mean   Median   SD     SEM    N                   Mean        Median          SD          SEM

  Died    154       0.5    0        13.7   1.1    115          -5.6          -4            10.7         1.0   

  Lived   818       -2.1   0        -2.1   0.5    831          -6.2          -5            13.5         0.5   
  ------------------------------------------------------------------------------------------------------------------

  ------------------------------------- ------------------------------------ ---------------------------------------- ---------------------------------------
  ![](media/image11.wmf)Placebo/Lived   ![](media/image12.wmf)Placebo/Died   ![](media/image13.wmf)Carvedilol/Lived   ![](media/image14.wmf)Carvedilol/Died

  ------------------------------------- ------------------------------------ ---------------------------------------- ---------------------------------------

[]{#__RefHeading___Toc26746871 .anchor}Figure 8. Distribution of changes
in heart rate (CAPRICORN)

Histograms are based on the change from baseline to the last available
heart rate, analyzed separately for subjects who lived or died in each
treatment group.

### Safety

Overall adverse event rates were similar on placebo (79%) and carvedilol
(80%). Adverse events seen in at least 2% of subjects and more common on
carvedilol than placebo (after rounding to the nearest 1%) are listed in
Table 12.

[]{#__RefHeading___Toc26746885 .anchor}Table 12. Common adverse events
(CAPRICORN)[^12]

+---------------+-------+---------+-----------------+-------+---------+
|               | Pl    | Car     |                 | Pl    | Car     |
|               | acebo | vedilol |                 | acebo | vedilol |
|               |       |         |                 |       |         |
|               | N=984 | N=975   |                 | N=984 | N=975   |
+===============+=======+=========+=================+=======+=========+
| Hypotension   | 12%   | 18%     | Syncope         | 2%    | 4%      |
+---------------+-------+---------+-----------------+-------+---------+
| Dizziness     | 11%   | 15%     | Anemia          | 2%    | 4%      |
+---------------+-------+---------+-----------------+-------+---------+
| Dyspnea       | 9%    | 10%     | Depression      | 2%    | 3%      |
+---------------+-------+---------+-----------------+-------+---------+
| Asthenia      | 6%    | 7%      | Renal failure   | 1%    | 3%      |
+---------------+-------+---------+-----------------+-------+---------+
| Bradycardia   | 4%    | 7%      | Postural        | 1%    | 2%      |
|               |       |         | hypotension     |       |         |
+---------------+-------+---------+-----------------+-------+---------+
| Pulmonary     | 3%    | 4%      |                 |       |         |
| edema         |       |         |                 |       |         |
+---------------+-------+---------+-----------------+-------+---------+

Serious adverse events were reported by 44% of subjects on placebo and
41% of subjects on carvedilol. The only serious adverse events more
common on carvedilol after rounding to the nearest 1% were pulmonary
edema (3% vs. 4%), syncope (\<1% vs. 1%), and hypotension (\<1% vs. 1%).

A similar proportion of subjects in both groups was discontinued for
adverse events.

# CHAPS

## Study title

SB-105517/RSD-101V83/1/CPMS-071: Double-blind, randomized, parallel
group study to investigate the effects (during treatment phase and
subsequent follow-up) of treatment with carvedilol (2.5 mg i.v. followed
by oral administration of 6.25 mg b.i.d. to 25 mg b.i.d.for up to 6
months) in comparison to those of placebo on the clinical course in
patients with acute myocardial infarction.

## Sources

The description of the study protocol and its results is based upon the
final study report, dated 14 August 1995. The study protocol was not
provided. SAS datasets were provided.

## Design

### Population

Subjects were to be age 18 to 80, with 30 minutes to 24 hours of chest
pain, ECG change, and cardiac enzymes all consistent with myocardial
infarction.

Exclusions were (1) contraindications to alpha- or beta-blockers, (2)
pregnancy or childbearing potential, (3) cardiomyopathy or pericarditis
within 1 month, (4) major cardiac surgery within 1 month, (5) Killip
class IV shock or heart failure, (6) bradycardia or conduction
abnormalities, (7) significant valve disease, (8) blood pressure outside
90-220/\<120 mmHg, (9) aneurysm, (10) thromboembolism, (11) exercise
limited by peripheral vascular disease, (12) obstructive airway disease,
(13) insulin-dependent diabetes, (14) renal failure, (15) hepatic
impairment, and (16) need for alpa-blockers, beta-blockers, or calcium
channel blockers.

### Procedures

Qualified subjects were randomized to placebo or carvedilol for up to 24
weeks. Randomization was stratified for anterior or inferior location of
index MI, and for use of thrombolytics. Post-hospitalization visits were
scheduled for 2, 6, 12, and 24 weeks. Subjects completing 24 weeks
discontinued treatment, but were followed at 3-month intervals.

Treatment consisted of carvedilol 2.5 mg iv over 15 minutes, then at 4
hours, carvedilol 6.25 mg bid for 2 days, then 12.5 mg bid until the
first post-hospitalization visit, then 25 mg bid if the blood pressure
was \>120/95 mmHg and heart rate \>55 bpm.

Thrombolysis was at the discretion of the physician. Aspirin 150 mg was
given unless contraindicated. Pre-existing therapy with nitrates,
digitalis, diuretics, and ACE inhibitors was permitted, but diuretics
were to be discontinued within 72 hours.

### End points

The primary end point was time to the first event of cardiac death,
heart failure, reinfarction, unstable angina, emergent
revascularization, stroke, ventricular arrhythmia requiring treatment,
or need for new or increased cardiovascular therapy (diuretics other
than for hypertension and after 24 hours, ACE inhibitor, digitalis, or
antiarrhythmics).

At 75 subjects per group, the study was sized to detect (with 80% power
and alpha=0.05) a decrease in event rate from 30% to 10%.

Secondary end points were, in the finest tradition of carvedilol
studies, numerousall-cause mortality, graded treadmill exercise (8
parameters), 24-hour ECG (11 parameters), radionuclide ventriculography
(13 parameters), echocardiography (15 parameters)and with no
prespecified plan for their interpretation.

### Administration

This was a single-center study (London) with no committees.

### Amendments

No protocol amendments are described.

## Conduct

Enrollment for CHAPS was from 11 February 1992 to 20 September 1994.

A total of 151 subjects were said to have been randomized, but 1 never
received study drug. Disposition is as shown in Table 13.

[]{#__RefHeading___Toc26746886 .anchor}Table 13. Disposition of subjects
(CHAPS)[^13]

+------------------------------------+-------------+------------------+
|                                    | Placebo     | Carvedilol       |
|                                    |             |                  |
|                                    | N=74        | N=77             |
+====================================+=============+==================+
| Discontinued in hospital           | 6           | 4                |
|                                    |             |                  |
| Adverse events                     | 4           | 1                |
|                                    |             |                  |
| Inclusion/exclusion                | 2           | 1                |
|                                    |             |                  |
| Death                              |             |                  |
+------------------------------------+-------------+------------------+
| \< 2 weeks                         | 7           | 5                |
|                                    |             |                  |
| Adverse events                     | 0           | 1                |
|                                    |             |                  |
| CABG                               | 1           | 0                |
|                                    |             |                  |
| Protocol violation                 | 1           | 0                |
|                                    |             |                  |
| Subject request                    | 0           | 1                |
|                                    |             |                  |
| Inclusion/exclusion                |             |                  |
+------------------------------------+-------------+------------------+
| \< 12 weeks                        | 6           | 4                |
|                                    |             |                  |
| Adverse events                     | 1           | 1                |
|                                    |             |                  |
| Death                              | 0           | 1                |
|                                    |             |                  |
| Loss to follow-up                  |             |                  |
+------------------------------------+-------------+------------------+
| \< 24 weeks                        | 11          | 5                |
|                                    |             |                  |
| Adverse events                     | 0           | 1                |
|                                    |             |                  |
| Non-compliance                     |             |                  |
+------------------------------------+-------------+------------------+

The reviewers\' analysis of disposition is shown in Figure 9.

  -----------------------------------------------------------------------
  ![](media/image15.wmf)

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746872 .anchor}Figure 9. Disposition of subjects
(CHAPS)

Reviewers\' analysis based on 147 subjects (71 on placebo and 76 on
carvedilol) for whom a starting date could be determined. The figure
shows the fraction of subjects on placebo or carvedilol in any of a set
of mutually exclusive states as a function of time.

The study was completed free of events by 68% of subjects on carvedilol
and 47% of subjects on placebo. Although there are differences in the
proportion of subjects withdrawn for non-compliance, the majority of the
difference is in the proportions having end point adverse events.

Five subjects were not analyzed for effectiveness. Two subjects in each
group were determined not to have had a myocardial infarction and one
was excluded for renal failure. In that the decision to treat had
already been made, it is inappropriate to refer to the subsequent
analysis as \"intent to treat\".

## Results

### Baseline characteristics

The two groups were similar with respect to baseline and demographic
characteristics. The median age was 60 years, 83% were male, 61% were
Caucasian, 38% were Asian, and 51% had anterior myocardial infarctions.
Almost all received thrombolysis (97%, mostly streptokinase), with a
median time of \<4 hours from onset of pain. The median time from onset
of pain to enrollment was 17 hours. Although the median blood pressures
in the two groups were very close, 24% of subjects on placebo were
classified as hypertensive vs. 9% on carvedilol. Diabetes was also more
common on placebo (18%) than on carvedilol (12%).

### Concomitant medications

Coronary vasodilators were used by 80% of subjects. Diuretics were used
by 25% on carvedilol vs. 14% on placebo. Only 6 subjects were receiving
ACE inhibitors at baseline, and only 4 were receiving digitalis.

All subjects received aspirin, and 96% received heparin.

About 90% of subjects in the carvedilol group were receiving the lower
dose (12.5 mg bid) of study drug.

### Primary end points

The sponsor\'s analysis of the primary end point is shown in Table 14.

[]{#__RefHeading___Toc26746887 .anchor}Table 14. Primary end point
events (CHAPS)[^14]

+--------------------+----------+------------+----------+------------+
|                    | T        |            | F        |            |
|                    | reatment |            | ollow-up |            |
|                    | phase    |            |          |            |
+====================+==========+============+==========+============+
|                    | Placebo  | Carvedilol | Placebo  | Carvedilol |
|                    |          |            |          |            |
|                    | N=71     | N=75       | N=71     | N=75       |
+--------------------+----------+------------+----------+------------+
| Any                | 31       | 18         | 3        | 10         |
+--------------------+----------+------------+----------+------------+
| Cardiac death      | 3        | 2          | 1        | 0          |
+--------------------+----------+------------+----------+------------+
| Heart failure      | 5        | 5          | 2        | 1          |
+--------------------+----------+------------+----------+------------+
| Reinfarction       | 8        | 4          | 0        | 1          |
+--------------------+----------+------------+----------+------------+
| Unstable angina    | 6        | 3          | 0        | 7          |
+--------------------+----------+------------+----------+------------+
| Revascularization  | 2        | 0          | 0        | 0          |
+--------------------+----------+------------+----------+------------+
| Stroke             | 1        | 0          | 0        | 1          |
+--------------------+----------+------------+----------+------------+
| Vent arrhythmia    | 1        | 0          | 0        | 0          |
+--------------------+----------+------------+----------+------------+
| CV therapy         | 5        | 4          | 0        | 0          |
+--------------------+----------+------------+----------+------------+

The life table analyses are shown in Figure 10.

  -----------------------------------------------------------------------
  ![](media/image16.png){width="4.420138888888889in"
  height="2.2256944444444446in"}

  -----------------------------------------------------------------------

[]{#__RefHeading___Toc26746873 .anchor}Figure 10. Primary end point
(CHAPS)

Sponsor\'s analyses of time to first cardiovascular event.

A true intent-to-treat analysis was not performed.

### Secondary end points

There were only 5 deaths on treatment, all judged to be cardiovascular,
so no formal comparison was made.

Exercise tolerance testing was performed at the end of hospitalization,
at 3 months, and at 6 months. No formal analysis was performed but total
exercise time at least trends in favor of placebo, as do times to onset
of angina and 1 mm ST depression.

Twenty-four hour Holter ECGs revealed consistently lower heart rate in
subjects on carvedilol. The number of ischemic episodes detected was
very low, with no consistent pattern by visit or treatment. PVCs were
somewhat more common on placebo, but couplets and runs of ventricular
tachycardia showed no consistent pattern.

Ventriculography and echocardiography showed no consistent treatment
effects.

### Other analyses

### Safety

Adverse events led to withdrawal of 48 subjects, 30 on placebo. There
were 6 other events considered serious, not leading to withdrawal.
Almost all such events were cardiovascular events captured in the
primary end point.

Non-cardiovascular events were relatively uncommon.

# Conclusions

The approved indication for carvedilol, in mild to severe heart failure,
is to increase survival and to reduce hospitalization. With submission
of the CHAPS and CAPRICORN studies, the sponsor seeks to extend the
indication to patients with left ventricular dysfunction following
myocardial infarction.

As a pilot study, CHAPS is intriguing, but the large discontinuation
rate makes it difficult to interpret. The bulk of the case rests upon
the much larger and better executed CAPRICORN study.

CAPRICORN was originally designed with all-cause mortality as its sole
primary end point. The composite of mortality plus cardiovascular
hospitalization was one of several secondary end points. The composite
end point later became a co-primary end point, with alpha assigned 0.045
to the composite and 0.005 (0.004 after planned interim analysis) to
all-cause mortality.

In making the change in end points, the goal of 633 events (now death
plus hospitalization) was unchanged. The additional hospitalization
events reduced the required enrollment from about 2600 to 1850, and
CAPRICORN was stopped soon after the end point amendment.

Thus, the power was very low for detecting a 23% reduction in the hazard
ratio for all-cause mortality. It is unclear why so little alpha was
allocated to all-cause mortality without planning more events (should
have been about 900, rather than 633) to ensure adequate study power.
Probably, the expectation was that carvedilol would have similarly sized
effects on mortality and cardiovascular hospitalization.

There is no issue regarding the end point of mortality plus
cardiovascular hospitalization. This end point, in which the majority of
the alpha was spent, is only a slight lean in favor of carvedilol.

The only issue is what to make of the finding on all-cause mortality.
From a strict frequentist viewpoint, the answer is clearly in favor of
the null hypothesis. This study had alpha of 0.004 invested in the final
analysis of mortality and the final p-value was 0.031, almost 8-fold
greater.

However, the Agency has acted as if studies all implicitly have
alpha=0.05 for mortality, independent of the primary end point. Against
alpha=0.05, the observed p=0.031 is encouraging, if not strongly so,
that this represents a reproducible result. Considered in the context of
the large p-value (0.27) for the other primary end point, however, the
study-wise type I error rate is much greater than 0.05, so the overall
statistical significance is far from what is conventionally expected.
Thus, CAPRICORN failed to yield a statistically conclusive finding.

Thus, the first interesting regulatory issue is whether one should
really interpret studies as having \"extra alpha\" available for the
\"discovery\" of a mortality effect. If, so, is the \"extra alpha\" as
much as 0.031? Does it matter that the \"discovery\" takes place in a
study that failed on its primary end point?

Without taking a position with regard to the \"extra alpha\" issue, the
reviewers consider other aspects of the mortality finding and its
possible interpretation.

First, the finding appears to be consistent across many pre-specified
subgroups. These are listed in Table 5 on page
[8](#__RefHeading___Toc26746878) and Figure 2 on page
[9](#__RefHeading___Toc26746865).

Second, the finding of a reduction in sudden death and a reduction in
death from worsening heart failure appears to be consistent with
previous study results, especially COPERNICUS.

The reviewers extended these observations by examining time to events of
mortality and cardiovascular hospitalization for subjects who had one or
the other or both events. These data are shown in Table 10 on page
[12](#__RefHeading___Toc26746883). The numbers of subjects who died with
or without cardiovascular hospitalization were smaller on carvedilol,
but the time to cardiovascular hospitalization tended to be longer on
placebo, regardless of mortal outcome. Among subjects who died, the
*mean* time to death was longer on carvedilol for subjects without
antecedent cardiovascular hospitalization, but longer on placebo for
subjects with such a hospitalization. The time from hospitalization to
death was also longer on placebo. The *median* time to death was longer
on placebo, among subjects who died, regardless of cardiovascular
hospitalization. Thus, there are some *internal* inconsistencies between
the overall mortality result and expected correlates.

And there is an *external* inconsistency between CAPRICORN and
COPERNICUS in effects on cardiovascular hospitalizationa trend of an
increased time to hospitalization on carvedilol in COPERNICUS and a
trend for a decreased time to hospitalization on carvedilol in
CAPRICORN.

If the effect of carvedilol on mortality in CAPRICORN were reproducible,
what would it mean?

First, if the finding of lower mortality were a reproducible result of
this study, the result may be substantially attributable to the
difference in blood pressure, rather than any special property of
carvedilol. Subjects in CAPRICORN were not, generally, hypertensive, by
the usual (arbitrary) criteria, but there is a trend for greater effects
in subjects at higher baseline blood pressure.

Second, any effect seen in CAPRICORN may be indistinguishable from the
effect in COPERNICUS. COPERNICUS demonstrated that carvedilol could
reduce total mortality in subjects with heart failure remote from any
myocardial infarction. In COPERNICUS, the two survival curves diverged
after about 2-3 months. In comparison, Figure 1 on page
[7](#__RefHeading___Toc26746864) shows that in CAPRICORN, the survival
curves do not diverge before about 6 months, suggesting one is seeing
the \"COPERNICUS effect\" in subjects who survive and mature from their
index infarction. It is difficult to see how the earlier and broader use
of carvedilol is beneficial.

[^1]: Thus the Agency was only notified of the changes after they were
    implemented.

[^2]: Sponsor\'s analysis.

[^3]: Distinct subjects in dataset MEDO with positive begin date
    (TRBEGSD) or end date (TRENDSD) and TRTXT matching {BETA-BLOCKER,
    BETA BLOCKER, ATENOLOL, ATENELOL, B BLOCKER, B-BLOCKER, B-BLOQ,
    METOPROLOL, CARVEDILOL, PROPRANOLOL, TENORMIN, NEOBLOC, NEOBLOCK,
    SELO-ZOK, SELOKEEN, TENOMIN, LABETOLOL, BISOPROLOL, PROPONOLOL,
    ATENOLOLI, METAPRALOLI, ATENOLLOLI, ATENTOLOL, ATHENOLOL, SELOKEN,
    BETALOC, BETALOK, BETALOKI, BETA ADRENERGIC, AIENOLOL, TENORMINE,
    KREDEX, KNEDEX, DIMITON, BELOC, BELOCZON, LOPRESSOR, LOPRESOR,
    METAPROPOLI, METROPOLOL, PROPOLOL, PROPRENOLOL, SUMIAL, DERALIN,
    OBSIDANI, SOTALOL, SORACOR, SOTALOLI, SOTALEX}.

[^4]: Distinct subjects in dataset MEDO with positive begin date
    (TRBEGSD) or end date (TRENDSD) and drug class (TRSCT) matching
    {CONVERTING ENZYME BLOCKERS, RENIN-ANGIOTENSIN SYSTEM AGENTS}.

[^5]: Sponsor\'s analyses, confirmed by the reviewers\' analyses.

[^6]: Reviewers\' analyses.

[^7]: Sponsor\'s analysis, confirmed by reviewers\' analysis.

[^8]: Sponsor\'s analysis is same as reviewers\' analysis of
    investigator\'s assessment as recorded in the DIED dataset.

[^9]: Sponsor\'s analysis

[^10]: Reviewers\' analysis.

[^11]: Reviewers\' analysis.

[^12]: Sponsor\'s analysis. Event rates are rounded to the nearest 1%
    and then only events more common on active drug are displayed.
    \"Peripheral vascular disorder\" (2% vs. 3%) was dropped from the
    table as too vague.

[^13]: Sponsor\'s analysis.

[^14]: Sponsor\'s analysis.