Thumbs up/Thumbs down – July 2004 VALUE and MATCH: An era of comparative clinical trials Eric J Topol MD Provost and Chief Academic Officer Chairman, Department

Thumbs up/Thumbs down – July 2004

VALUE and MATCH: An era of comparative clinical trials

Eric J Topol MDProvost and Chief Academic OfficerChairman, Department of Cardiovascular MedicineCleveland Clinic FoundationCleveland, OH

Robert M Califf MDProfessor of MedicineAssociate Vice Chancellor for Clinical ResearchDirector, Duke Clinical Research InstituteDuke University Medical CenterDurham, NC


VALUEValsartan Antihypertensive Long-Term

Use Evaluation

MATCHManagement 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

End point Valsartan Amlodipine Hazard ratio (95% CI)

p

Primary composite, n (%)

810 (10.6) 789 (10.4) 1.04(0.94-1.15)

0.49

Cardiac mortality, n (%)

304 (4.0) 304 (4.0) 1.01(0.86-1.18)

0.90

Cardiac morbidity, n (%)

586 (7.7) 578 (7.6) 1.02(0.91-1.15)

0.71

Lancet 2004; 363


VALUE: Systolic BP over time by treatment group

Time point Valsartan Amlodipine p

Baseline 154.5+19.0 154.8+19.0 <0.0001

One month 152.7+17.5 148.7+17.4 <0.0001

Three months

149.2+19.5 145.4+16.1 <0.0001

Final 139.3+17.6 137.5+15.0 <0.0001

Lancet 2004; 363


VALUE: Secondary and prespecified end points

End point Valsartan Amlodipine HR(95% CI)

p

Fatal and nonfatal MI, n (%)

369 (4.8) 313 (4.1) 1.19(1.02-1.38)

0.02

Fatal MI, n (%) 66 (0.86) 64 (0.84) 1.04(0.74-1.47)

0.81

Fatal and nonfatal heart failure, n (%)

354 (4.6) 400 (5.3) 0.89(0.77-1.03)

0.12

Fatal and nonfatal stroke, n (%)

322 (4.2) 281 (3.7) 1.15(0.98-1.35)

0.08

New-onset diabetes, n (%)

690 (13.1) 845 (16.4) 0.77(0.69-0.86)

<0.0001

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

End point Hazard ratio (95% CI) p

Composite cardiac events

0.90 (0.79-1.03) 0.111

Stroke 1.02 (0.81-1.28) 0.899

Death 0.96 (0.84-1.10) 0.566

MI 0.97 (0.80-1.19) 0.791

Heart failure 0.81 (0.66-0.99) 0.040

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

Outcome Clopidogrel alone,n=3802, n (%)

Clopidogrel plus aspirin, n=3797, n (%)

Primary end point

636 (16.7) 596 (15.7)

Any stroke 347 (9.1) 339 (8.9)

Death 201 (5.3) 201 (5.3)

Life-threatening bleeding

49 (1.3) 96 (2.5)

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 aspirin may have skewed results

Topol


MATCH: Interpreting the results

"I don't object to doing a clinical trial where you answer a question that advances knowledge, which this trial did."

• Bothersome if results spun to say clopidogrel alone should be used in preference to aspirin

- Califf


MATCH: What about the CHD trials?

How do the results square with the coronary disease trials, which show the combination better than aspirin alone?

•CURE and CREDO—with aspirin as background therapy—strong evidence of increased efficacy with clopidogrel added, with little bleeding risk

• In MATCH, hemorrhagic stroke not the reason for the lack of efficacy


MATCH: Aspirin resistance

Lack of regard for aspirin resistance

•As high as 15% to 25% of patients with a platelet response not as expected

•Higher event rates in patients on antiplatelet therapy without adequate platelet suppression

"It's out there, it's dangling, and it's a highly significant public-health issue."

- Topol


MATCH: Aspirin resistance

Need for National Institutes of Health or clinical trialist consortium to address the issue

•Need to keep pressure on to solve the problem of a lack of biological response to aspirin or clopidogrel in certain patients


MATCH: Decision

I would give this one thumb up, because it is a kooky design, but it does add something.

- Califf

"Things are getting tough when we have to give it one thumb for publishing the results . . . but it did a lot of things right."

• One thumb up• Need to make sure the blueprints of the house are right before the house is built

- Topol

Documents

Thumbs up/Thumbs down – July 2004 VALUE and MATCH: An era of comparative clinical trials Eric J Topol MD Provost and Chief Academic Officer Chairman, Department