heartbeat – jan 2003 allhat allhat and allhat-llt valentin fuster md director, cardiovascular...

Heartbeat – Jan 2003

ALLHAT

ALLHAT and ALLHAT-LLT

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY

Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, MA

James Ferguson MDAssociate Director, CardiologySt Luke's Episcopal Hospital and Texas Heart InstituteHouston, TX

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, NY


ALLHAT

ALLHAT and ALLHAT-LLT

Special Guest Commentator

Thomas G Pickering MD, PhDDirector, Integrative and Behavioral Cardiovascular

Health Program And Hypertension ProgramMount Sinai Medical CenterNew York, NY


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

ALLHAT: Trial design

•33 357 patients age >55 with hypertension and 1 additional risk factor

•Randomized to:

chlorthalidone (12.5 mg to 25 mg/day, n=15 255)

amlodipine (2.5 mg to 10 mg/day, n=9048)

lisinopril (10 mg to 40 mg/day, n=9054)

•Primary end point: fatal CHD or nonfatal MI


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

Secondary outcomes: Amlodipine vs chlorthalidone

End point

Amlodipine (%)

Chlorthalidone (%)

Relative risk

p

6-year rate of heart failure

10.2 7.7 1.38 (1.25-1.52)

<0.001

JAMA 2002; 288:2981-2997


ALLHAT

Summary

Why did diuretics do so well in this population, when we've all been talking about how great the ACE inhibitors are?

How do we unravel this surprising finding?

Fuster


ALLHAT

A negative study

"I was frustrated by the authors immediately portraying this paper in public policy and economic terms."

"I am by no means convinced that this study is anything other than what you might normally call a negative study."

"I'm not convinced the discrepancies between the drugs are as obviously apparent as claimed."

Weber


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

Heart-failure protection

"I was astonished with the heart-failure result."

It seems an ACE inhibitor would be a superior protector against heart failure

Could the chlorthalidone be masking the symptoms of heart failure and resulting in missed diagnoses?

Weber


ALLHAT

Blood-pressure effect

It is possible the blood-pressure difference explains some, if not most, of the final results

There was a consistent difference throughout the trial

ACE inhibitors have been shown to be more effective in younger patients, and the age of the trial participants may be a factor in ALLHAT

Pickering


ALLHAT

Blood-pressure difference

Can the blood pressure have had significant impact when the difference was so small?

Blood-pressure difference compared with chlorthalidone

Amlodipine: +0.8 mm Hg

Lisinopril: +2.0 mm Hg

Fuster


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

ALLHAT: Masking heart failure

It is possible the diuretics were masking some of the clinical manifestations of heart failure

"I don't think that [ALLHAT] means that we should throw out all the new forms of therapy and go back to treating everybody with diuretics."

Ferguson


ALLHAT

ALLHAT: Understanding the biology

"Is it the blood-pressure control or is it the specific agents?"

We have confounding results and don't have the absolute answer right now

We haven't had a chance to examine all the different subgroups yet

Ferguson


ALLHAT

ALLHAT: Fundamental principles

"We've been going along fat, dumb, and happy thinking we've got all these great new forms of therapy and they're so much better than what we had before. And now we've got to reexamine that."

We need to apply the principles of risk stratification to the world of hypertension

Ferguson


ALLHAT

ALLHAT: A surprise

"I think we were all somewhat surprised."

Consensus of meta-analyses was CCBs are better at preventing stroke, while ACE inhibitors are better at preventing coronary events when compared to standard diuretic and beta-blocker treatment

Pickering


ALLHAT

ALLHAT: Elderly population

ALLHAT had a relatively elderly population:

mean age: 67 years 57% of patients >65

We don't have as many comparative trials in the elderly

Pickering


ALLHAT

ALLHAT: Heart failure

Increased heart failure was a factor involved in stopping the doxazosin arm of ALLHAT

"It may be that the diuretic tends to reduce sodium retention whereas some of these agents may be associated with sodium retention if not given in combination with a diuretic."

Pickering


ALLHAT

HOPE: Primary end points

0

2

4

6

8

10

12

14

16

18

Even

ts (

%)

CV death MI Stroke Combined

Ramipril Placebo

N Engl J Med 2000; 342(3):145-153


ALLHAT

African American population

There seems to be an inconsistency between HOPE and ALLHAT concerning ACE inhibitors

ALLHAT was designed to have a large black population (35%) in the study

ACE inhibitors may be less effective in this population

Weber


ALLHAT

Overinterpreting the findings?

30% to 40% of the benefit seen in HOPE may come from lowering blood pressure

Can argue that in the white cohort in ALLHAT, ACE inhibitors may have reduced coronary events 5% to 8% once blood pressure is factored in

"I am rather concerned that the authors of the study [ALLHAT]have perhaps overinterpreted their own findings" Weber


ALLHAT

Biochemical changes

Past studies with diuretics suggested that one of the problems with the drug was an effect on elements like fasting glucose, potassium, etc

These may increase risk for people with hypertension

Does ALLHAT tell us we should stop worrying so much about these things?

Fuster


ALLHAT

New-onset diabetes

In SHEP, diabetics did well on chlorthalidone

Beta blockers may help prevent new-onset diabetes

ACE inhibitors have also been linked to prevention of new-onset diabetes

Pickering


ALLHAT

JAMA 2002; 288:2981-2997

ALLHAT: Fasting glucose levels

0

5

10

15

20

25

30

35

Fasti

ng g

lucose >

126

mg/dL (

%)

Baseline 2 years 4 years

Chlorthalidone Lisinopril Amlodipine


ALLHAT

Three patients

Which would be the first drug of choice?

Patient 1: Age 65; BP 170/100; no evidence of atherosclerotic disease

Patient 2: Age 65; BP 170/100; previous MI, good LVF

Patient 3: Age 65; BP 170/100; previous stroke


ALLHAT

First patient





ALLHAT

First patient: First drug

Weber: Start with calcium channel blocker, maybe a diuretic in a black patient

Pickering: Diuretic

Ferguson: Diuretic

Cannon: Diuretic, maybe a generic ACE inhibitor

Fuster: ACE inhibitor in the past–not sure now


ALLHAT

Digesting ALLHAT

We must teach our colleagues that the last word is not yet in on all this

"This is a very complicated story, ALLHAT, we're going to have to take a few months to fully digest it."

Weber


ALLHAT

Second patient





ALLHAT

Second patient: First drug

Weber: ACE inhibitor

Pickering: Beta blocker

Ferguson: ACE inhibitor

Cannon: Beta blocker, followed by ACE inhibitor

Fuster: ACE inhibitor


ALLHAT

Third patient





ALLHAT

Third patient: First drug

According to PROGRESS study, you should use a combination of ACE inhibitor and a diuretic

Likely to start with diuretic for older patient and ACE inhibitor for younger, but will end up with both

Pickering


ALLHAT


This patient is a quandary right now, having both manifest atherosclerotic disease and hypertension

I am still biased toward ACE inhibitors and will make that the first line of therapy

Cannot lose sight of the underlying atherosclerotic disease

Ferguson


ALLHAT


I want to finish up with both ACE inhibitor and a diuretic (PROGRESS trial) so it doesn't matter which I start with

"Someone who comes in with 170 systolic, you aren't going to get him down to 140 with 1 drug anyway."

We all seem likely to end up with an ACE inhibitor and a diuretic as a combination

Weber


ALLHAT


Start with an ACE inhibitor for the vascular disease risk and then titrate to blood pressure with diuretic as a follow-up drug

Cannon


ALLHAT

Drug choice based on patient

An ACE inhibitor followed by a diuretic

Seems that for a patient age 65 with

•No manifestation of disease–start with a diuretic

•CAD with good VF–ACE inhibitor

•After a stroke–combination of ACE inhibitor and diuretic

Fuster


ALLHAT

Implications of ALLHAT

ALLHAT suggested that all of these drugs are similar in their effect

"Tragically, ALLHAT never examined the sorts of combinations that we use."

ALLHAT is complicated by the fact the patients weren't treated in the way they would be in the real world

Weber


ALLHAT

ALLHAT mortalityC

um

ula

tive m

ort

ality

rate

Years to death0 1 2 3 4 5 6 7

0

.05

.1

.15

.2

.25

.3

HR (95% CI) p

A/C 0.96 (0.89-1.02) 0.20

L/C 1.00 (0.94-1.08) 0.90

ChlorthalidoneAmlodipineLisinopril

ALLHAT trial site


ALLHAT

ALLHAT-LLT: Trial design

•10 355 patients age >55 with hypertension and 1 additional risk factor and moderate hypercholesterolemia

•Randomized to:

pravastatin (40 mg/day, n=15 255)

usual care

•Primary end point: all-cause mortality


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

HPS: Mortality results

0

2

4

6

8

10

12

14

16

Event

rate

(%

)

All-cause mortality Vascular death

Simvastatin Placebo

Lancet 2002; 360:7-22


ALLHAT

ALLHAT-LLT: Statin use

0

10

20

30

40

50

60

70

80

90

% o

n s

tati

n

2 years 4 years 6 years

Statin arm Usual care arm

JAMA 2002; 288:2998-3007


ALLHAT

ALLHAT-LLT: Evolving standard of care

"We've been going along thinking that the statins are the answer to all of our atherosclerotic disease problems, and they're not."

If usual standard of care means 30% are on statins anyway, it's hard to improve on that with a statin

Ferguson


ALLHAT

ALLHAT-LLT: Open label

ALLHAT-LLT was not a double-blind trial, it was open-label

Lots of dropouts (22.6% of statin arm came off their drug over the course of the trial)

The big difference with other statin trials lies in the study design

Cannon


ALLHAT

ALLHAT-LLT: Designing clean studies

Must construct clean, well-designed studies that can give meaningful results even in the face of an improving standard of care

ALLHAT-LLT was also underpowered due to lack of enrollment

Cannon


ALLHAT

ALLHAT-LLT: Crossovers

It may become more difficult to see differences in the future, the real danger is crossovers

An unblinded trial makes it much easier to use the study drug as part of usual care

Fuster


ALLHAT

ALLHAT-LLT: LDL-CLD

L-C

in

mg

/dL

0 2 4 6100

110

120

130

140

150

Usual care

Pravastatin

Year of blood draw

7% *

11%

16%

23%

28% 30%

* Percent decrease from baseline.


ALLHAT

Summary: ALLHAT

In a hypertensive population, a diuretic was as good as the use of amlodipine and lisonipril

"Diuretics may not be as bad as I thought."

The results may be due in part to blood-pressure effects

Fuster


ALLHAT

Summary: ALLHAT-LLT

"It's not a good study."

There was a lot of crossover, and that makes it difficult to draw conclusions

It hasn't changed my opinion on statins

Fuster


ALLHAT

Final word: Ferguson

In both studies our preconceived notions were wrong

The studies reinforce which mechanisms we should be targeting

•ALLHAT: focus on blood pressure in hypertensive patients

•ALLHAT-LLT: should still be treating cholesterol is a priority

Ferguson


ALLHAT

Final word: Pickering

ALLHAT makes me think people should be using diuretics more

•Current trends show diuretics being used less and less

ALLHAT-LLT won't change the way I use statins in my practice

Pickering


ALLHAT

Final word: Cannon

"One will be much more apt to turn to diuretics and include them as part of combination therapy."

The lesson from LLT is that one wants to do a clean trial as the way to examine if something is beneficial

Cannon


ALLHAT

Next program

AHA 2002 Part 2

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY

Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, MA

James Ferguson MDAssociate Director, CardiologySt Luke's Episcopal Hospital and Texas Heart InstituteHouston, TX

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, NY

heartbeat – jan 2003 allhat allhat and allhat-llt valentin fuster md director, cardiovascular...

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