# Presentation: 337898

## Is there evidence to justify different claims for different drug classes? 

**Presentation to:**
**Cardiovascular & Renal Drugs Advisory Committee**
**Food & Drug Administration**
**Rockville MD, June 15, 2005**
**Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C.**

## Blood Pressure Lowering Treatment Trialists’ Collaboration1995-2005Secretariat: The George Institute, University of Sydney & Royal Prince Alfred HospitalPrincipal sponsor: National Health & Medical Research Council of Australia

## 1st cycle published Lancet 2000; 355:1955-64
2nd cycle published Lancet 2003; 362:1527-35
29 randomised trials 
162,341 patients
More than 700,000 patient years

- 2nd cycle published *Lancet *2003; 362:1527-35
- 29 randomised trials
- 162,341 patients
- More than 700,000 patient years

- Analysis cycles

## Active vs. control
ACE-I vs placebo
CA vs placebo
More intensive vs less intensive
ARB vs. other regimen
Active vs. active
ACE-I vs diuretic/beta-blocker*
CA vs diuretic/beta-blocker*
ACE-I vs CA

- ACE-I vs placebo
- CA vs placebo
- More intensive vs less intensive
- ARB vs. other regimen
- Active vs. active
- ACE-I vs diuretic/beta-blocker*
- CA vs diuretic/beta-blocker*
- ACE-I vs CA

- Treatment comparisons

## Active vs. control
ACE-I vs placebo
CA vs placebo
More intensive vs less intensive
ARB vs. other regimen
Active vs. active
ACE-I vs diuretic/beta-blocker*
CA vs diuretic/beta-blocker*
ACE-I vs CA

- ACE-I vs placebo
- CA vs placebo
- More intensive vs less intensive
- ARB vs. other regimen
- Active vs. active
- ACE-I vs diuretic/beta-blocker*
- CA vs diuretic/beta-blocker*
- ACE-I vs CA

- Treatment comparisons

## Most trials compared treatment regimens rather single drugs
Regimens were usually based on a specific agent with the addition of others as required for BP control
In active vs. active comparisons, the control condition was pre-specified as diuretic- or beta-blocker-based therapy (mostly diuretic)

- Regimens were usually based on a specific agent with the addition of others as required for BP control
- In active *vs.* active comparisons, the control condition was pre-specified as diuretic- or beta-blocker-based therapy (mostly diuretic)

- Treatment comparisons

## ACE inhibitor vs. diuretic/beta-blocker

| 
 | Total
participants | Major 
events |
| --- | --- | --- |
| AASK | 877 | NA |
| ALLHAT | 24309 | 1195 |
| ANBP2 | 6083 | 509 |
| CAPPP | 10985 | 698 |
| STOP-2 | 4418 | 897 |
| UKPDS-HDS | 758 | 141 |
| Total | 47430 | 6031 |

## Calcium antagonist vs. diuretic/beta-blocker

|  | Total 
participants | Major 
events |
| --- | --- | --- |
| AASK | 658 | NA |
| ALLHAT | 24303 | 3704 |
| CONVINCE | 16476 | 729 |
| ELSA | 2334 | 60 |
| INSIGHT | 6321 | 407 |
| NICS-EH | 239 | 23 |
| NORDIL | 10881 | 803 |
| SHELL | 1882 | 172 |
| STOP-2 | 4409 | 910 |
| VHAS | 1414 | 29 |
| Total | 68449 | 6837 |

## ACE inhibitor vs. calcium antagonist

| 
 | Total
participants | Major
events |
| --- | --- | --- |
| AASK | 653 | NA |
| ABCD (H) | 470 | 75 |
| ABCD (N) | 480 | 76 |
| ALLHAT | 18102 | 2838 |
| JMIC-B | 1650 | 88 |
| STOP-2 | 4401 | 887 |
| Total | 25756 | 3964 |

## Active vs. activeStroke

-  RR (95% CI)

-  Favours
- first listed

-   Favours
- second listed

- 0.5

- 1.0

- 2.0

- Relative Risk

- BP
- difference
- (mm Hg)

-  1.09 (1.00,1.18)

-  ACE vs. D/BB

-  0.93 (0.86,1.00)

-  CA vs. D/BB

-  1.12 (1.01,1.25)

-  ACE vs. CA

- 2/0

- 1/0

- 1/1

- Active *vs.* active*Stroke*

## Active vs. activeCoronary heart disease

-  RR (95% CI)

-  Favours
- first listed

-    Favours
- second listed

- BP
- difference
- (mm Hg)

- 0.5

- 1.0

- 2.0

- Relative Risk

-  0.96 (0.88,1.04)

-  1.01 (0.94,1.08)

-  0.98 (0.91,1.05)

-  ACE *vs.* CA

-  CA *vs.* D/BB

-  ACE *vs. *D/BB

- 2/0

- 1/0

- 1/1

- Active *vs.* active*Coronary heart disease*

## Active vs. activeHeart failure

-  RR (95% CI)

-  Favours
- first listed

-    Favours
- second listed

- BP
- difference
- (mm Hg)

- 0.5

- 1.0

- 2.0

- Relative Risk

-  1.07 (0.96,1.19)

-  ACE *vs.* CA

-  CA *vs.* D/BB

-  ACE *vs. *D/BB

-  1.33 (1.21,1.47)

-  0.82 (0.73,0.92)

- 2/0

- 1/0

- 1/1

- Active *vs.* active*Heart failure*

## Active vs. activeComposite major CVD events

-  RR (95% CI)

-  Favours
- first listed

-    Favours
- second listed

- BP
- difference
- (mm Hg)

- 0.5

- 1.0

- 2.0

- Relative Risk

-  ACE *vs.* CA

-  CA *vs.* D/BB

-  ACE *vs. *D/BB

-  0.97 (0.92,1.03)

-  1.04 (1.00,1.09)

-  1.02 (0.98,1.07)

- 2/0

- 1/0

- 1/1

- Active *vs.* active*Composite major CVD events*

## Active vs. activeComposite major CVD events (diabetes subgroups)

- Risk ratio

- 0.25

- 0.5

- 1

- 2

** ****0.90 (0.74,1.11)**

** ****1.04 (0.98,1.04)**

** ****1.02 (0.95,1.10)**

** ****1.04 (0.99,1.10)**

** ****0.92 (0.79,1.07)**

** ****0.99 (0.92,1.07)**

**p homog =0.20**

**p homog =0.83**

**p homog =0.37**

**2.2/0.3**

**1.4/0.2**

**ACE-I vs. D/BB**

**Diabetes**

**No diabetes**

**CA vs. D/BB**

**Diabetes**

**No diabetes**

**ACE-I vs. CA**

**Diabetes**

**No diabetes**

******BP**
**(****mmHg****)**

**RR(95%CI)**

**Favours**
**first listed**
** **

**Favours**
**second listed**
** **

**0.7/-0.8**

**1.1/-0.4**

**1.6/1.2**

**1.3/0.9**

**Overall **

**Overall **

**Overall **

**Arch Int Med 2005: *****in press***

## ARB-based regimens vs. othersComposite outcomes (diabetes subgroups)

- 0.5

- 1

- 2

**Major CVD**

**Diabetes**

**No diabetes**

-  0.90 (0.82,0.99)

-  0.90 (0.81,1.00)

**-2.1/-0.9**

**-1.4/-0.6**

- p homog=0.94

**CV deaths**

**Diabetes**

**No diabetes**

-  0.99 (0.77,1.28)

-  0.95 (0.81,1.12)

**-2.1/-0.9**

**-1.4/-0.6**

- p homog=0.79

**Total mortality**

**Diabetes**

**No diabetes**

**-2.1/-0.9**

**-1.4/-0.6**

-  0.91 (0.75,1.10)

-  0.97 (0.86,1.09)

- p homog=0.55

- ARB-based regimens vs. others*Composite outcomes** **(diabetes subgroups)*

******BP**
**(mmHg)**

**RR(95%CI)**

**Favours**
**ARB**
** **

**Favours**
**Other**
** **

**Overall **

**Overall **

**Overall **

**Arch Int Med 2005: *****in press***

## Calcium antagonist and D/BB-based regimens may be more effective than ACE inhibitors for stroke prevention 
ACE inhibitors and D/BB regimens are more effective than CA-based regimens for heart failure prevention
No differences between regimens in effects on coronary heart disease

- ACE inhibitors and D/BB regimens are more effective than CA-based regimens for heart failure prevention
- No differences between regimens in effects on coronary heart disease

- Conclusions

## For total cardiovascular events,   there were very similar effects of:
ACE inhibitor-
calcium antagonist-
D/BB-based regimens
ARB-based regimens also reduced total CV events
Effects of all drug classes similar in diabetic and non-diabetic patients

- ACE inhibitor-
- calcium antagonist-
- D/BB-based regimens
- ARB-based regimens also reduced total CV events
- Effects of all drug classes *similar* in diabetic and non-diabetic patients

- Conclusions

## Independent drug effects?

**Primary focus of debate for past decade, with no consensus**
**Main hypothesis concerns potential advantages of agents that inhibit the renin angiotensin system**
**Do ACE inhibitors and angiotensin receptor blockers confer benefits “beyond blood pressure reduction”**

## Effects of RAS inhibitors

**In trials of active *****vs.***** active regimens**
**No clear advantage of ACE inhibitor-based regimens compared with D/BB-based regimens**
**But moderate differences between regimens in BP lowering effects**** **
**In trials of ARB-based regimens**
**Uncertainty as to whether benefits are greater than those expected given the reduction in BP**

## Effects of RAS inhibitors

**New analysis**
**Effects of ACE-I and ARB-based regimen *****vs.***** any other comparator**
**Stratified by BP differences between randomized groups**
**Cause-specific outcomes: stroke, coronary heart disease, heart failure***
**    *****trials with calcium antagonist control treatment excluded from heart failure analyses, given clear evidence of differential effect of these agents**

## "This slide contains unpublished data.  If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

**"*****This slide contains unpublished data.  If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney*****."**

## "This slide contains unpublished data.  If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

## "This slide contains unpublished data.  If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

## "This slide contains unpublished data.  If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

## Conclusions

- For all regimens, size of BP reduction directly related to size of risk reduction
- For coronary heart disease, BP- independent effect of ACE inhibitor-based regimens (about 10%)
- For stroke and heart failure, no clear evidence of BP-independent effects of either ACE-I or ARB-based regimens

## Conclusions

- In active *vs.* active comparisons, the independent effect of ACE-I-based regimens was obscured by weaker BP lowering properties
- Because of this practical limitation, therapeutic relevance is uncertain
- Combination therapy with an ACE inhibitor and other BP lowering agents may offer greatest protection

## Acknowledgements

- Coordinating center staff:
- Fiona Turnbull MD MPH
- Bruce Neal MD PhD MRCP
- Charles Algert MPH
- Mark Woodward PhD CStat
- John Chalmers MD PhD FRACP