TNT and WHS: Twists and turns at the 2005 ACC
Eric J Topol MD Provost and Chief Academic Officer Chair, 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
TNT Treating to New Targets
WHS Women's Health Study
Topics
Treating to New Targets
TNT
Treating to new targets
Parallel-group study randomizing stable CHD patients to a double-blind treatment with atorvastatin 10 mg or 80 mg (N Engl J Med 2005; published March 8)
Study aim
Primary hypothesis of TNT was that an incremental reduction in risk could be achieved by lowering LDL-cholesterol levels beyond the currently recommended minimum targets
Design
10 001 patients with clinically evident CHD, defined as previous MI, previous or present angina with evidence of atherosclerotic CHD, or having undergone a coronary revascularization procedure
Median follow-up of 4.9 years
Baseline and final LDL-cholesterol levels
Primary efficacy outcomes
Califf's conclusions
No difference in all-cause mortality
"If I didn't have a reduction in death, but I have a lower risk of heart attack or stroke, I'd take that."
Califf
Safety
Slightly higher rate of liver-function-test abnormalities
1.2% of patients treated with 80-mg atorvastatin had a persistent elevation in alanine aminotransferase, aspartate aminotransferase, or both, compared with 0.2% of patients treated with 10-mg atorvastatin (p<0.001)
Cautious editorial
Bertram Pitt editorial
Questioned whether there would be any reductions in total mortality with high-dose statin therapy in stable CHD patients
Questioned whether TNT data are sufficient to alter clinical practice
Topol's thoughts
TNT results build on the results of the PROVE-IT TIMI-22 and REVERSAL studies
Mortality only issue left to be debated
"I look at this as a win. It confirms and extends the other trials."
Topol
Conspiracy theories
Issues have been raised by the public that the studies are part of a conspiracy to boost pharmaceutical sales
Data are very strong, even outside of influence of consultants and "big pharma"
Cost not likely to be an issue
Involving CRP reductions
Instead of a megadose of a statin, more prudent to assess benefit of reducing LDL to <70 mg/dL and CRP to <1.0 mg/dL
Reduction in MI and stroke is as big as statins vs placebo
"Big step forward in medicine."
Topol
Mortality data
Do you think there is any risk of cancer, suicide, or other causes of death with statins?
- Topol
No. I don't think we have any credible evidence that there is a problem.
- Califf
Remaining questions
"I am definitely a convert."
How much lower should LDL-cholesterol levels go?
How do we get this treatment out to the population who would really benefit?
Califf
Decision
Decision
Two thumbs up for TNT
- Topol and Califf
Women's Health Study
WHS
Women's Health Study: Design
Use of aspirin for primary prevention in women
(N Engl J Med 2005: published March 7)
39 876 initially healthy women 45 years of age or older
Randomized to 100 mg of aspirin on alternate days or placebo
Monitored for first major CV event (nonfatal MI, nonfatal stroke, or death from CV causes)
10-year follow-up
Cardiovascular end points
Stroke end points
Misleading results
One thumb up . . .
Antithrombotic Trialist Collaboration suggests doses less than 75 mg/day not as effective
Very low-risk patient population
Don't know if gender explains the results
Topol
What do the results mean?
"It is confusing."
Age was the risk factor that determined whether women benefited
Issue of dosing very important—different dose for different people
Califf
Interpreting the results
If it was too low a dose, why was there a significant reduction in stroke?
- Topol
Unfortunate that such a large trial would be initiated with aspirin dose less than 75 mg
Interpreting the results
Trial "spun" as a win for aspirin despite not meeting its primary end point
WHS could be interpreted as a negative study, that is, "Low-dose aspirin shouldn't be given to women, period."
Topol
Interpreting the results
For low-risk patients, those with <1% per year risk of a vascular event, there is no treatment that has a major effect on outcome.
- Califf
But the Framingham score is not the most accurate assessment of risk.
- Topol
Treating patients
Risk of intracerebral hemorrhage
The more hypertension is the dominant risk factor, the more the focus should be on treating the blood pressure and lipids.
Where diabetic-type risk factors are dominant, then focus should be on "paralyzing the platelets."
Califf
Gender differences
Average age in WHS is 54 years
But it is the women >65 years that benefit the most:
34% reduction in MI.
30% reduction in stroke.
26% reduction in cardiovascular events.
Aspirin dose correct as long as it is given to elderly women
Regulatory point of view
Aspirin not approved for primary prevention
Five previous studies, but little data on its use as a primary-prevention treatment strategy in women
Is the WHS contradictory to previous trials? Should it be sanctioned as a treatment strategy in older women?
Clinical practice
Younger women without a multiplicity of risk factors should not be given aspirin.
- Topol
"I hope the result in the younger, low-risk women is right."
- Califf
Younger baby-boomers will respond to this negative information about aspirin
Decision
One thumb, maybe one-and-a-half, up.
Vexing that the dose of aspirin was so low in such an important study
- Califf