Lecture 15-CVD Clinical trials

Question 1

why conduct clinical trials?

Answer 1

GHIMPS
G-inform guidelines
H- determine health policy
I-influence individual choices
M-market advantage
P- improve clinical practice
S- set standards

Question 2

5 modes of clinical trial design

Answer 2

prospective 
randomised
placebo controlled
double blind
sufficient statistical power

Question 3

why do you need sufficient statistical power?

Answer 3

• enough numbers to give confidence in result

- enough people to detect small difference which will be valuable in long run

Question 4

who creates the hypothesis? and why?

Answer 4

an independent steering/management committee

• independent of the drug company,
• overarching management of trial as it goes on

Question 5

who creates the defined and reliable endpoints and why do you need them?

Answer 5

• independent endpoint adjudication committee

- standard the doctors use to diagnose should be the same–>good quality data

Question 6

2 main reason why independent data safety monitoring committee intervenes

Answer 6

1. when they need to stop trials because its harming people

2. drug treatment is so good that results need to be published- unethical that rest of population doesn’t receive drug

Question 7

what committee gets to see who is taking what drug?

Answer 7

the independent data safety monitoring committee

Question 8

who analyses the data?

Answer 8

independent statistical analysis committee

- experts in stats

Question 9

who writes the papers?

Answer 9

publications committee

Question 10

compare VA and advance trials - treatment

Answer 10

BP drugs (both

Question 11

compare VA and advance trials - control

Answer 11

VA- placebo (didn’t know whether BP drugs would work, needed placebo)
Advance- background therapy (we know drugs work, unethical not to give)
- 80% of people taking drug are on statins, RAS drugs to reduce BP

Question 12

what is the problem with background therapy?

Answer 12

mortality without new treatments is already on 2.5%

• if new drug wants to improve situation, already a low base
• how do you tell whether the drug is working significantly?

Question 13

compare VA and advance trials - patients

Answer 13

VA- 143 (smaller number)

Advance- 11430 (more patients)

Question 14

compare VA and advance trials - duration

Answer 14

VA- 2 years

Advance- 4.3 years (since patients are on background therapy, need bigger trials over a longer period of time)

Question 15

compare VA and advance trials - treatment effect

Answer 15

VA- 20mmHg reduction in Diastolic BP- (bigger reduction)
- CV deaths (active vs control 0 v 6%)- even though small trials over short time, bigger difference
advance- 2mmHg reduction in diastolic BP (lower reduction)
- active vs control (4 vs 5%) small change

Question 16

problem with inadequate statistical power

Answer 16

false negatives can be avoided with large trials

- otherwise even with good outcomes, you believe that it is not significant enough due to low statistical power

Question 17

hard vs soft/surrogate endpoints define

Answer 17

hard- e.g. death, MI
soft/surrogate- associated with risk in theory but not shown to translate into e.g. deaths, MI
e.g. cardiac mass, microalbuminuria, pulse wave velocity, nocturnal BP

Question 18

what endpoints give way to substudies?

Answer 18

surrogate/soft endpoints

Question 19

reason for substudies

and problems with substudies

Answer 19

can add value
- genetic analysis and explanatory detail on a smaller scale, subset of population, more detailed
PROBLEMS
- can mislead- post hoc (after event), unrandomised- if thing you are examining wasnt initially randomised between the two groups, there will be bias when doing these studies

Question 20

what is a new trend for trials?

Answer 20

routine treatment in high risk subjects compared to targeted treatment for those at high risk

• people who have identified themselves at risk for CVD get drug (e.g. smoking, diaebetes, have had BP treatment) even though they have low BP currently
• dont use fit and healthy people

Question 21

what is the polypill? what does it do?

Answer 21

mixture of drugs that improve different CVD risk factors

• aspirin- anti inflammatory
• statin- reduce cholesterol
• ACE inhibitor- reduce BP
• umpire study

Question 22

where is the polypill given?

Answer 22

cheap countries that can’t afford latest medicine

Question 23

concept of renal denervation

Answer 23

when sympathetic nerves activated–>kidneys retain salt and water and release renin (increase BP)
- therefore cut off nerve supply to kidney–>reduce BP–>destroy renal nerves without damaging renal artery

Question 24

adrenergic overdrive in hypertension

Answer 24

evidence of adrenergic overdrive in hypertension- excess sympathetic activity going into kidney

Question 25

what was the potential for renal denervation?

Answer 25

• reduce renal vascular resistance, renin levels, renal afferent nerve signals
• improve renal function
• increase sodium excretion

Question 26

what were the 3 trials for renal denervation?

Answer 26

symplicity HTN-1 trial
- open label cohort (everyone knew who gets treatment) 
-no independent controls
-results- very big reduction
symplicity HTN-2 trial
-  randomised open label trials
- controls had drugs alone
- results- big decrease in systole 
symplicity HTN-3 trial
- prospectiv,e randomised, sham-controls (got needle but no zap) 
- results- no significant difference

Question 27

what was the reason that renal denervation didnt work in the HTN-3 trial?

Answer 27

compliance

• people weren’t taking their drugs before the renal denervation
• once they got the zap, started taking drugs (therefore drugs probably reduced the BP and not the zap)

Question 28

what do we rely on for future CV clinical trials?

Answer 28

depending on the emergence of a potential game changing blockbuster treatment- new concepts coming in