thumbs up/thumbs down – feb 2003 allhat allhat: optimal first-step therapy for hypertension eric j...

Thumbs up/Thumbs down – Feb 2003

ALLHAT

ALLHAT: Optimal first-step therapy for hypertension

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

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


ALLHAT

Randomized designof ALLHAT

High-risk hypertensive patients

Consent / Randomize

(42 418)

AmlodipineChlorthalidoneDoxazosinLisinopril

Eligible for lipid-lowering

Not eligible for lipid-lowering

Consent / Randomize (10 355)

Pravastatin Usual care

Follow for CHD and other outcomes until death or end of study (up to 8 yrs).


ALLHAT

A horse race

Each class of antihypertensive is represented by a drug, and the losers drop out as events are accrued

Primary end point: fatal CHD or nonfatal MI

All major clinical end points were measured in minimal detail

Califf


ALLHAT

Secondary drug protocol

Step 2 agents: Dose 1* Dose 2* Dose 3*

Reserpine 0.05 qdor 0.1 qod

0.1 qd 0.2 qd

Clonidine (oral) 0.1 bid 0.2 bid 0.3 bid

Atenolol 25 qd 50 qd 100 qd

Step 3 agent:

Hydralazine 25 bid 50 bid 100 bid

*All doses in mg


ALLHAT

ALLHAT: Trial design

•42 418 patients age >55 with hypertension and 1 additional risk factor

•623 sites:

United States

Canada

Puerto Rico

US Virgin Islands


ALLHAT

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0 1 2 3 4

Cu

mu

lati

ve e

ve

nt

rate

Years of Follow-up

doxazosin

chlorthalidone

C: 15,268D: 9,067

12,990 7,382

9,4435,285

4,8272,654

2,0101,083

Rel risk 1.25

z = 6.77, p < 0.0001

95% CI1.17-1.33

JAMA. 2000;283:1967-1975

Doxazosin CVD end point


ALLHAT

JAMA 2002; 288:2981-2997

ALLHAT: Primary end point

0.0

2.0

4.0

6.0

8.0

10.0

12.0

Events

(%

)

Chlorthalidone Lisinopril Amlodipine


ALLHAT

JAMA 2002; 288:2981-2997

Lisinopril secondary end points

0

1

2

3

4

5

6

7

8

9

6-y

ear

even

t ra

te

(per

10

0 p

ers

on

s)

Heart failure Stroke

Chlorthalidone Lisinopril


ALLHAT

JAMA 2002; 288:2981-2997

Amlodipine secondary end points

0

2

4

6

8

10

12

6-y

ear

even

t ra

te

(per

10

0 p

ers

on

s)


Chlorthalidone Amlodipine


ALLHAT

JAMA 2002; 288:2981-2997

ALLHAT: Fasting glucose levels

0

5

10

15

20

25

30

35

Fasti

ng g

lucose >

126 m

g/dL (

%)

Baseline 2 years 4 years



ALLHAT

Stroke risk: Lisinopril vs chlorthalidone

Subgroup Relative risk 95% CI

Nonblack 1.00 0.85-1.17

Black 1.40 1.17-1.68

JAMA 2002; 288:2981-2997


ALLHAT

JAMA 2002; 288:2981-2997

ALLHAT: Glomerular filtration rate

60626466687072747678

Fil

trati

on r

ate

m

L/

min

per

1.7

3

sq m

Baseline 2 years 4 years



ALLHAT

ALLHAT-LLT: Primary results

0

2

4

6

8

10

12

14

16

6-y

ear

even

t ra

te/

100 p

ati

en

ts

Mortality CHD and nonfatal MI

Pravastatin Usual care

JAMA 2002; 288:2998-3007


ALLHAT

ALLHAT-LLT: Disappointing

Second largest statin trial after HPS

"[It's] disappointing that it didn't provide true consistency and only with this bouillabaisse pooling stuff do you get the same relative effect."

Topol


ALLHAT

ALLHAT: Points of contention

Why did lisinopril increase heart failure and stroke?

This is directly opposite of the results from HOPE

PEACE and EUROPA are looking at ACE inhibitors as a key preventive tactic

"This backfired terribly in ALLHAT."

Topol


ALLHAT

Active control trial

The other drugs were only less effective than the diuretic, not increasing risks for the patients

The "soft underbelly" of HOPE was whether the patients were being adequately treated with regard to their other risk factors

If EUROPA and PEACE are negative, either HOPE was wrong or ramipril is "a magic potion"

Califf


ALLHAT

Using less ramipril

I've gone from requiring ramipril use to making it optional

"I think we have to say this is a piece of data that moves back toward less radical enthusiasm about the ACE-inhibitor class."

Califf


ALLHAT

JAMA 2002; 288:2981-2997

ALLHAT: Blood pressure

125

130

135

140

145

150

0 1 2 3 4 5

Years

Systo

lic B

P (

mm

Hg

)Chlorthalidone Lisinopril Amlodipine


ALLHAT

Genetics of hypertension

Studies suggest the genetic defect of essential hypertension alpha —adducin Gly460Trp would be particularly responsive to thiazide diuretic

Topol


ALLHAT

Stroke risk: Lisinopril vs chlorthalidone

Subgroup Relative risk 95% CI

Nonblack 1.00 0.85-1.17

Black 1.40 1.17-1.68

JAMA 2002; 288:2981-2997


ALLHAT

JAMA 2002; 288:2981-2997

ALLHAT: Blood pressure

125

130

135

140

145

150

0 1 2 3 4 5

Years

Systo

lic B

P (

mm

Hg

)Chlorthalidone Lisinopril Amlodipine


ALLHAT

JAMA 2002; 288:2981-2997

Amlodipine secondary end points

0

2

4

6

8

10

12

6-y

ear

even

t ra

te

(per

10

0 p

ers

on

s)


Chlorthalidone Amlodipine


ALLHAT

Edema or heart failure?

There was no objective measure of function to diagnose heart failure

A substudy was commissioned to have records independently reviewed

All the results are not in, but so far the substudy suggests that there is more than just edema going on

Califf


ALLHAT

Surprising increase in heart failure

The increase in heart failure for both classes of drugs (ACE inhibitor and CCB) was a very surprising finding

• Lisinopril 19% increased risk

• Amlodipine 38% increased risk

"You would have thought both drugs would not have done this."

Topol


ALLHAT

Bad choice of second drug

Critics say the second drug after ACE inhibitor would be a diuretic, forbidden by the trial

Most doctors in the US probably don't use a diuretic as the second drug

"I think no matter how you slice the loaf here the answer is that the underused diuretics, which are a lot cheaper, are at least as good and almost certainly better."

Califf


ALLHAT

A class effect?

Most doctors use hydrochlorothiazide as a diuretic

This could be a chlorthalidone-specific result, you can't be sure

"We have examples where drugs in the same class don't get the same results."

Califf


ALLHAT

Striking secondary outcomes

The media loved that a cheaper drug came out better

I wasn't enthusiastic about the trial when I was on the NIH advisory committee reviewing the trial

"The secondary outcomes made for all the spice here. If you were

to just go by the primary outcome, though, you wouldn't be able to differentiate the treatments."

Topol


ALLHAT

Public health

Why not use a cheaper drug that is just as good? It's a dominant treatment

A company trying to get labelling with this primary outcome might have trouble getting approval from the FDA

"We have examples where drugs in the same class don't get the same results."

Califf


ALLHAT

An easy choice

There is a value judgment being made among the secondary outcomes

"I think the majority of people, if you said, 'Look, I can give you this thing for 2 cents a day, or I can give you this thing for a buck and a half a day, and here are the expected outcomes, which would you buy?' I don't think that's a hard choice."

Califf


ALLHAT

Inadequate treatment

"None of these drugs are very good, they all have some untoward effects, unfortunately. You're picking your poison in some respects."

This study reinforces that there is inadequate treatment of blood pressure.

"A lot of people are walking around with very high blood pressure still, despite therapy." Topol


ALLHAT

Lowering blood pressure

"I think that people that are most critical of doctors trying to lower blood pressure are people that have never actually worked in a clinic trying to get blood pressure down."

It takes the doctor and patient working together to get blood pressure down

We usually need more than 2 drugs

Califf


ALLHAT

Genomics approach to hypertension

Genomics will allow us to move past the trial and error approach

"$37 billion a year it costs to treat hypertension and we're not

even doing a very good job of doing it. We've got to have a better strategy and almost any strategy would be better than what we have today."

Topol


ALLHAT

Interpersonal approach

People will round numbers down for patients who are frustrated at not getting hypertension under control to avoid adding more drugs drugs

Lowering blood pressure is very complicated and interpersonal

Califf


ALLHAT

Two thumbs up

Topol: "Don't you think this is as good as it gets for hypertension and clinical trials?"

• Two thumbs up

Califf: "I think it's as good as it gets."

• Two thumbs up


ALLHAT

A new approach

"The system we have now, where companies not only fund trials but decide what the questions are is not the right way to do it"

Doctors and patients want to know which is the best choice among the treatments that work?

Most companies avoid head-to-head trials and try to game them even when they agree

Califf


ALLHAT

Honest broker

NIH or other agencies as an honest broker is the model to pursue in the future

"If a drug is a winner it ought to prevail in a direct comparison without the type of

engineering that can occur with interested sponsors."

Topol


ALLHAT

Pricing

The price of a drug should be a function of how much it contributes

"The way it is now, people are having to decide what to take and what to buy without any knowledge in many fields of which one is really better."

In multiple sclerosis, for example, there are 4 drugs and no one knows which is really better

Califf


ALLHAT

ALLHAT: Optimal first-step therapy for hypertension

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

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

thumbs up/thumbs down – feb 2003 allhat allhat: optimal first-step therapy for hypertension eric j...

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