Lecture 15-CVD Clinical trials Flashcards
why conduct clinical trials?
GHIMPS G-inform guidelines H- determine health policy I-influence individual choices M-market advantage P- improve clinical practice S- set standards
5 modes of clinical trial design
prospective randomised placebo controlled double blind sufficient statistical power
why do you need sufficient statistical power?
- enough numbers to give confidence in result
- enough people to detect small difference which will be valuable in long run
who creates the hypothesis? and why?
an independent steering/management committee
- independent of the drug company,
- overarching management of trial as it goes on
who creates the defined and reliable endpoints and why do you need them?
- independent endpoint adjudication committee
- standard the doctors use to diagnose should be the same–>good quality data
2 main reason why independent data safety monitoring committee intervenes
- 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
what committee gets to see who is taking what drug?
the independent data safety monitoring committee
who analyses the data?
independent statistical analysis committee
- experts in stats
who writes the papers?
publications committee
compare VA and advance trials - treatment
BP drugs (both
compare VA and advance trials - control
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
what is the problem with background therapy?
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?
compare VA and advance trials - patients
VA- 143 (smaller number)
Advance- 11430 (more patients)
compare VA and advance trials - duration
VA- 2 years
Advance- 4.3 years (since patients are on background therapy, need bigger trials over a longer period of time)
compare VA and advance trials - treatment effect
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
problem with inadequate statistical power
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
hard vs soft/surrogate endpoints define
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
what endpoints give way to substudies?
surrogate/soft endpoints
reason for substudies
and problems with substudies
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
what is a new trend for trials?
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
what is the polypill? what does it do?
mixture of drugs that improve different CVD risk factors
- aspirin- anti inflammatory
- statin- reduce cholesterol
- ACE inhibitor- reduce BP
- umpire study
where is the polypill given?
cheap countries that can’t afford latest medicine
concept of renal denervation
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
adrenergic overdrive in hypertension
evidence of adrenergic overdrive in hypertension- excess sympathetic activity going into kidney
what was the potential for renal denervation?
- reduce renal vascular resistance, renin levels, renal afferent nerve signals
- improve renal function
- increase sodium excretion
what were the 3 trials for renal denervation?
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
what was the reason that renal denervation didnt work in the HTN-3 trial?
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)
what do we rely on for future CV clinical trials?
depending on the emergence of a potential game changing blockbuster treatment- new concepts coming in
