PPP and Complement Inhibition

Clinical Trial Commentary

Dr Eric TopolChairman and Professor, Department of CardiologyDirector of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic

Dr Robert CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Where we are nowPPP

Aspirin has been shown to be quite effective in secondary prevention, but there has been significant controversy about primary prevention

Physicians’ Health Study – stopped early, substantial reduction in non-fatal MI but an excess of hemorrhagic strokes (non-significant trend)

British study – did not show dramatic difference in primary prevention

Primary Prevention Project

Innovative approach: recruiting from daily practice

Open 22 factorial design in 4495 people with one or more major cardiovascular risk factor (hypertension, hypercholesterolemia, diabetes, obesity, family history of premature myocardial infarction, or old age) but no prior events or symptomatic angina

The PPP trial evaluated low-dose aspirin (100 mg/day) and vitamin E (300 mg/day)in a randomized, non-blinded study

PPP

ResultsPPP

Aspirin (n=2226)

No aspirin (n=2269)

Relative risk (95% CI)

Total cardiovascular events

6.3% 8.2% 0.77 (0.62–0.95)

Total mortality 2.8% 3.4% 0.81(0.58-1.13)

Cardiovascular mortality

0.8% 1.4% 0.56(0.31–0.99)

All stroke 0.7% 1.1% 0.67 (0.36–1.27)

Roncaglioni et al. Lancet 2001; 357:89-95

Design

“The ability to inexpensively randomize a large number of patients and get a result that’s this dramatic not only is an important finding for clinical practice, but also, I think, points the way to a system that we might use to more rapidly evaluate the effectiveness of simple interventions in primary care practice.”

Dr Robert CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

PPP

Issues with the trial

Primary endpoint not significantCV death, non-fatal MI, non-fatal stroke

Relative risk = 0.71 (0.48–1.04)

Trial stopped earlyenrolled 4495 instead of the projected 7500 patients owing to the results of other trials that may not be germane

PPP

Choice of endpoint

Does total mortality trump a primary endpoint?

Should you pull out cardiovascular mortality?

Do partial studies weaken the implications of secondary endpoints?

PPP

Available dose

100-mg dose isn’t available in the US

Effectiveness of 80-mg dose seems to have been corroborated by several studies

Hypertension may be a contraindication for aspirin use (Hypertension Optimal Treatment trial)

PPP

Optimal dose

The optimal dose remains unresolved

Currently anywhere from 80 mg to 325 mg has been validated in one way or another

Correct dose of aspirin could be more effective for developing countries than the latest drug

A simple dose-comparison study is being proposed

PPP

Conclusions

CaliffPPP and HOT push him to recommend aspirin as primary prevention

TopolAspirin shows implications in many diseases other than cardiology

This is convincing, but would be more convincing if the trial had gone to completion

PPP

Pexelizumab (Alexion/Procter & Gamble):An anti-inflammatory C5 inhibitor monoclonal antibody fragment

914 patients scheduled for CABG surgery, or CABG plus valve replacement enrolled, randomized to:

• placebo • pexelizumab in a 2.0 mg/kg bolus• pexelizumab in a 2.0 mg/kg bolus followed

by a 24-hour infusion of pexelizumab at 0.05 mg/kg/h

Complement inhibition

Pexelizumab study

Results

30-day safety and efficacy follow-upResults only available from a press release

CABG-only group (n=796) Pexelizumab Placebo

Death 0.4% 1.9%

Non-Q-wave MI(CK-MB >100 ng/mL)

2.7% 8.0%

Death or MI (non-Q-wave or Q-wave)

7.8% 13.2%

Complement inhibition

Press release, Jan 26, 2001: Alexion Pharmaceuticals, Inc.

Perioperative MI

An area that has not been sufficiently studied

C5 inhibition may reduce perioperative MI

The mechanism is still unclear

Will it be verified?

What were the changing definitions of MI?

Complement inhibition

“I think it is important for cardiologists to be aware that there’s tremendous activity right now on the issue of preventing necrosis in the setting of bypass surgery, [because] the complexity of the operation and the morbidity is still quite high. This is despite clear improvements in the technology and the skill of the surgeons and the operating teams. But they’re just operating on very high-risk patients as we all know. So there’s a real niche for this type of therapy if it really works.”

Dr Robert Califf

Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Complement inhibition

Preventing necrosis

Defining myocardial necrosis

Cardioplegia makes EKGs very unreliable because the majority of patients have some elevation of markers of necrosis

Where do you define the threshold?

How much necrosis do you need to prevent?

CARDINAL trials: direct angioplasty and thrombolysis, should add to the picture

There are multiple methods of inhibiting complement that are under investigation

Complement inhibition

Future of CABG

Bypass has been neglected for development of therapeutics and adjunctive medications

The dangers of periprocedural MI during CABG need to be examined, it isn’t revered enough

We may see a resurgence of CABG as technology allows for less severe patients to be operated on

Complement inhibition

Cognitive decline

Percentage of patients who suffered a declineof 20% or more in cognitive function frompre-CABG baseline

Complement inhibition

Time frame Patients suffering decline

Discharge 53%

6 weeks 36%

6 months 24%

5 years 42%

Newman M, et. al. N Engl J Med 2001; 344(6):395-402

Cognitive decline questions

Is this all related to bypass surgery, or is it associated with severe athereosclerosis?

How much is due to the bypass machine?

Does off-pump surgery prevent cognitivedecline?

Does complement inhibition help?

What genetic markers may indicate risk?

Complement inhibition