VALUE研究和MATCH研究
VALUE and MATCH: An era of comparative clinical trials
Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, OH
Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC
VALUE Valsartan Antihypertensive Long-Term Use Evaluation
MATCH Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke
Topics
Valsartan Antihypertensive Long-Term Use Evaluation
VALUE
VALUE: Goal
Trial designed to compare two treatment strategies: amlodipine (Norvasc?, Pfizer) and valsartan (Diovan?, Novartis). (Lancet 2004 Jun 19; 363:2022-31.)
STUDY AIM
If similar blood-pressure control could be achieved with both drugs, would there be any beneficial effect on cardiac end points with valsartan beyond blood-pressure lowering alone?
Primary end point a composite of cardiac morbidity or mortality
VALUE: Design
Trial involved 15 245 hypertensive patients with at least one high-risk feature, including CAD, previous stroke or TIA, peripheral vascular disease, or diabetes
Patients randomized to valsartan 80 mg or amlodipine 5 mg
Patients already on BP-lowering medications "rolled over" to either amlodipine or valsartan
At one month, if target BP not <140/90 mm Hg, patients up-titrated to valsartan 160 mg and amlodipine 10 mg; hydrochlorothiazide added in increasing doses if control not achieved
VALUE: Primary composite end point
Lancet 2004; 363
VALUE: Systolic BP over time by treatment group
Lancet 2004; 363
VALUE: Secondary and prespecified end points
Lancet 2004; 363
VALUE: Califf's conclusions
"Bringing blood pressure down quickly is important."
Early differences in BP lowering does make a difference
Amlodipine, if anything, looks better as monotherapy
Diabetes finding will affect some clinicians
Califf
VALUE: Topol's thoughts
"Usually I don't find hypertension so interesting, but this is a very interesting trial."
Control of BP with amlodipine better up front and throughout the trial
MI, stroke, and all-cause death better with amlodipine in the first three months
Topol
VALUE: Topol's thoughts
Overall, the trade-off appears to be less stroke, fewer infarcts with amlodipine, but more new-onset diabetes
Unsure how to interpret HF data
"To me, it looks pretty favorable for amlodipine, even though the trial appears to be spun to support a lack of differences."
Topol
VALUE: Blood-pressure control
Amlodipine, in this environment, does get the nod over valsartan
Results related to early difference in BP control
Pfizer continues to come out on top despite doing the "wrong trials"
Valsartan still a valuable drug, considering its low side-effect profile
Califf
VALUE: Drug or BP lowering?
But a 19% increase in fatal and nonfatal MIs and a 15% increase in fatal and nonfatal strokes? That doesn't speak well for valsartan.
- Topol
I don't see that as a huge rap on valsartan. It's a rap on not getting the blood pressure down.
- Califf
VALUE: Results after adjusting for BP differences
Lancet 2004; 363
VALUE: Admitting bias
This trial was sponsored by Novartis, and people, being wise to the ways of the world, will know it was spun a little bit.
- Califf
I'm glad you admit that.
- Topol
VALUE: Admitting bias
"I think some of the trials we've done, we've taken on the sponsor. It's important for investigators to stand up for what the findings are."
In VALUE, key end points don't look good for valsartan but you wouldn't have known that from investigators quoted in press releases
Topol
VALUE: Data out there
Savvy clinicians should be able to look at the data and know the CV results are heading in the wrong direction
Need for both drugs—suppress diabetes and protect against MI and stroke
Trials continue to support renin- angiotensin-system blockade to protect against diabetes
Topol
VALUE: Making an impact
Major message from this trial is to get the BP down and to keep it down
By lowering BP 5 to 10 mm Hg through a combination of diuretic, ACE inhibitor, or CCB, one could reduce the number of morbid events and hospital admissions
Big opportunities in hypertension management
Califf
VALUE: Decision
"This is a very rigorous, solid trial, and I would give it two thumbs up."
- Topol
"I would also give it two thumbs up, with one caveat . . ."
Should the trial have been stopped at six months due to the discrepancy in systolic BP?
- Califf
VALUE: Results
"The adage is don't ever stop a trial, unless it's something so highly compelling."
- Topol
"We probably need to move to a new standard for how we monitor trials."
- Califf
Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke
MATCH
MATCH: Design
Cerebrovascular trial presented at the 13th European Stroke Conference in Germany
7500 high-risk patients who had a recent TIA or stroke, with at least one high-risk feature
Patients randomized to aspirin 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy, for 18 months
Primary end point a composite of the first occurrence of MI, ischemic stroke, vascular death, or rehospitalization for an acute ischemic event
MATCH: Results
13th European Stroke Conference; May 12-15, 2004; Mannheim-Heidelberg, Germany.
MATCH: What do the results mean?
"It's like taking one leg away from a three-legged stool—I don't know how to make things stand."
Missing the aspirin-only study arm
Adds an interesting piece of information but I can't figure out what to do with it in clinical practice
Califf
MATCH: Strange trial design
Based on the CAPRIE data, if cost weren't an issue, you could make a case that clopidogrel might be better than aspirin in these patients. But cost is a big issue.
To use clopidogrel as a background therapy doesn't make sense
Flawed design, difficult to interpret the data
Many patients were taking aspirin before trial started—events on