heartbeat – june 2003 continental divide lionel opie md professor and head, heart research...
TRANSCRIPT
Heartbeat – June 2003
Continental Divide
Lionel Opie MDProfessor and Head, Heart Research InstituteUniversity of Cape TownCape Town, South Africa
Franz Messerli MDAssociate Section Head, HypertensionOchsner Clinic FoundationNew Orleans, LA
Joseph Izzo MDVice Chair, Department of MedicineSUNY at BuffaloBuffalo, NY
Continental Divide:Hypertension guidelines--US vs Europe
Heartbeat – June 2003
Continental Divide
Three key differences
•Simplified classification system
•Aggressive treatment recommendations
•What is the role of thiazide diuretics?
Heartbeat – June 2003
Continental Divide
Simplified BP classification
JNC 7
BP Classification SBP mm Hg DBP mm Hg
Normal <120 and <80
Prehypertension 120–139 or 80–89
Stage 1 hypertension 140–159 or 90–99
Stage 2 hypertension >160 or >100
Heartbeat – June 2003
Continental Divide
Aggressiveness and thiazide
How assertive should clinicians be in treating hypertension?
•How quickly clinicians should try to get to goal blood pressures?
What is the role of thiazide diuretics?
•Does JNC 7 say diuretics are preferred agents or are they just one recommendation of many?
Izzo
Heartbeat – June 2003
Continental Divide
Two quotes
"Thiazide-type diuretics should be used as initial therapy in most patients with hypertension, either alone or in combination."
JNC 7
"The major classes of hypertensive agents--diuretics, beta blockers, calcium antagonists, ACE inhibitors, ARBs--are suitable for initiation and maintenance of therapy"
European guidelines
Heartbeat – June 2003
Continental Divide
Problems with "prehypertensive"
Messerli
The prefix "pre" has negative connotations
"To my way of thinking, to label a person whose blood pressure is 120/80 as prehypertensive is simply inappropriate."
Framingham has shown that if you are age 50-55, the odds of becoming hypertensive in the next 25 years are >90%
Heartbeat – June 2003
Continental Divide
Integrated risk factors
Messerli
The European guidelines integrate additional risk factors better than JNC 7 for risk stratification
•Comorbidities
•Target organ disease
In fairness, JNC 7 is the short report
Heartbeat – June 2003
Continental Divide
Data beyond randomized trials
Messerli
European guidelines acknowledge event-based trials are too short to assess lifelong hypertension therapy
Used surrogate end points to supplement strong clinical end points
• Subclinical organ damage
•LVH
•Microalbuminuria
Heartbeat – June 2003
Continental Divide
Socioeconomic factors
Opie
Large differences in wealth and access in the US
European guidelines state up front that Europe is relatively homogenous and due to state health care, cost is not paramount
JNC 7 has no mention even of ethnic/racial differences, which we know govern many aspects of wealth and access
Heartbeat – June 2003
Continental Divide
Population issues
We don't know enough about the response rates of different populations
• Trends favor thiazide diuretics in blacks, ACE inhibitors in whites
The overarching principles don't change by race so should not form a fundamental basis for initial therapy
Socioeconomic issues can be somewhat addressed by generics
Izzo
Heartbeat – June 2003
Continental Divide
Population differences
The US population may not be similar in needs to the European population
• Obesity and salt intake are very different than in Northern Europe
Diuretics must be given along with other agents in the US to get good BP control
Control rates are better in the US than in Europe, possibly due to more aggressive treatment
Izzo
Heartbeat – June 2003
Continental Divide
Obesity and the metabolic syndrome
Messerli
"The European guidelines clearly state that treatment-induced alterations in cholesterol, potassium, glucose tolerance, etc, although they hardly can be expected to increase cardiovascular events during the short term of a trial, may have an impact during the longer course of the patient's life."
Heartbeat – June 2003
Continental Divide
JAMA 2002; 288:2981-2997
ALLHAT: De novo diabetes
0.0
2.0
4.0
6.0
8.0
10.0
12.0
Events
(%
)
Chlorthalidone Lisinopril Amlodipine
Heartbeat – June 2003
Continental Divide
Treating the metabolic syndrome
Messerli
"It was very disappointing for me to see that there are no guidelines given [in JNC 7] how to treat patients with the metabolic syndrome in terms of antihypertensive therapy."
Even in diabetic patients, thiazides lead the list of antihypertesnive drugs
Heartbeat – June 2003
Continental Divide
Indications for individual drug classes
JNC 7
Compelling indication
Initial therapy options
Clinical trial basis
Diabetes Thiazide, beta blocker, ACE inhibitor, ARB, CCB
NKF-ADA guideline, UKPDS, ALLHAT
Chronic kidney disease
ACE inhibitor, ARB
NKF guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent stroke prevention
Thiazide, ACE inhibitor
PROGRESS
Heartbeat – June 2003
Continental Divide
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
Heartbeat – June 2003
Continental Divide
Indication Clinical trial basis
Heart failure ACC/AHA Heart Failure Guideline,
MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES
Post-MI ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
High CAD risk ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
Diabetes NKF-ADA guideline, UKPDS, ALLHAT
Chronic kidney disease
NKF guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent stroke prevention
PROGRESS
Trial basis for treatment decisions
Heartbeat – June 2003
Continental Divide
JAMA 2002; 288:2981-2997
ALLHAT: Fasting glucose levels
0
5
10
15
20
25
30
35
Fasti
ng
glu
co
se
>1
26
mg
/d
L (
%)
Baseline 2 years 4 years
Chlorthalidone Lisinopril Amlodipine
Heartbeat – June 2003
Continental Divide
Compelling Indication
Diuretic BB ACEI ARB CCB AldoANT
HF * * * * *
Post-MI * * *
High coronary disease risk
* * * *
Diabetes * * * * *
Indications for individual drug classes
Heartbeat – June 2003
Continental Divide
ALLHAT: Blood sugar and diabetes
Blood sugar tends to be higher on thiazide, although the impact remains debatable
ALLHAT mean blood sugar:Thiazide: 126.3 mg/dLACE inhibitor: 121.5 mg/dL
New-onset diabetes:Thiazide: 11.6%ACE inhibitor: 8.1%
Izzo
Heartbeat – June 2003
Continental Divide
Attenuating the thiazide effect
ACE inhibitor or an ARB completely attenuates the hyperkalemia and hyperglycemia effects caused by diuretics
"I come back to the value of combination therapy and that's where the strength of both documents could lie."
Doctors should be thinking about combination drugs earlier
Izzo
Heartbeat – June 2003
Continental Divide
Inappropriate wording
Messerli
"Thiazide should be used in drug treatment in most patients, either alone or combined." -- JNC 7
JNC 7 doesn't prevent anyone from treating a patient with the metabolic syndrome with a thiazide alone
"Except nobody should do that. . . . This is inappropriate wording."
Heartbeat – June 2003
Continental Divide
Treating diabetic patients
Messerli
All the studies show 14% to 34% more new-onset diabetes in the diuretic or conventional therapy arm
Even in the INSIGHT study, new-onset diabetes was 23% higher in the diuretic arm
"Clearly I think this should be taken into account."
Heartbeat – June 2003
Continental Divide
Thiazide diuretic definitions
Opie
JNC 7 says "thiazide-type diuretics"
•What do you understand by low-dose thiazide?
•Are thiazide diuretics the same as chlorthalidone?
Heartbeat – June 2003
Continental Divide
Low-dose thiazide
We have defined lower dose as 12.5 or 25 mg of hydrochlorothiazide
Maximum dose we recommend is 50 mg
Little is known about 50-mg dose, since that hasn't been studied very recently, and the old studies were flawed
Izzo
Heartbeat – June 2003
Continental Divide
Chlorthalidone equivalency
No literature or good head-to-head trials on the equivalence of chlorthalidone and hydrochlorothiazide
"My own opinion is that the potency of hydrochlorothiazide is roughly half that of chlorthalidone."
Izzo
Heartbeat – June 2003
Continental Divide
Chlorthalidone dosing
ALLHAT doses are above the 25 mg of hydrochlorothiazide we typically employ
Chlorthalidone is somewhere between 150% and 200% more effective than the same milligram amount of hydrochlorothiazide
There is a lot of diuretic on board in these studies, and the hyperglycemia seems to be dose-dependent Izzo
Heartbeat – June 2003
Continental Divide
Treating diabetic patients
Messerli
MR FIT study found the mortality rate was unfavorable in the clinics using hydrochlorothiazide and favorable in the clinics using chlorthalidone
"We do not have any head-to-head comparisons, and we probably never will, but this is rather powerful evidence that the two drugs are not the same"
Heartbeat – June 2003
Continental Divide
Not enough data
Opie
No good dose-response data with diuretics
"Are you really suggesting we should preferentially use an agent we really don't know that much about?"
Heartbeat – June 2003
Continental Divide
Diuretic history
Diuretics were originally used in multiples of the doses used today (gave rise to the worries about side effects)
Doses were lowered over time without the guidance of controlled clinical trials
Found reasonable efficacy with lower doses
Izzo
Heartbeat – June 2003
Continental Divide
ACE-inhibitor history
ACE inhibitors also started with much higher doses than are used today
ACE inhibitors and ARBs may be dosed too low now since they have no dose-dependent side effects
"We do not have very good clinical pharmacology to back up any of these recommendations that we're making."
Izzo
Heartbeat – June 2003
Continental Divide
Head to head
Messerli
NIH spent $100 million on ALLHAT
For less than $1 million someone could do a simple head-to-head trial
•Chlorthalidone vs hydrochlorothiazide using simple surrogate end points
Heartbeat – June 2003
Continental Divide
Beta blockers
Opie
JNC 6 recommended diuretics and/or beta blockers as initial therapy
•What are the data for beta blockers reducing mortality?
JNC 7 downgraded beta blockers to the level of the other drugs
• What led to the downgrading of the beta blockers?
Heartbeat – June 2003
Continental Divide
Beta-blocker data
There were relatively poor data supporting beta blockers as a major approach
JNC 6 recommendation was not particularly supportable
Beta blockers are good to have as an option, especially with prevalence of cardiac disease, since the heart is their major target organ
Izzo
Heartbeat – June 2003
Continental Divide
Elderly
Opie
Both the European and the JNC 7 guidelines are focused on the elderly
•Some mention of teenagers
•Not much mention of the middle-aged (40-60) hypertension patients
Heartbeat – June 2003
Continental Divide
Uncomplicated hypertension
Messerli
Beta blockers are still lumped with ARBs, ACE inhibitors, calcium-channel blockers
Inappropriate because the evidence is meager for beta blockers in uncomplicated hypertension
•Three independent studies showing no risk reduction with beta blockers for noncardiac end points
Heartbeat – June 2003
Continental Divide
Beta blockers in cardiac disease
Messerli
Beta blockers make sense in the post-MI patient
Possibly in diabetes, but not in the cases of uncomplicated hypertension
"I think [beta-blockers] should have been kicked off, just the same as the alpha blockers were, of the basket in which the other drugs are in now. And this is true for both guidelines."
Heartbeat – June 2003
Continental Divide
Good indications for beta blockers
Messerli
Many good indications for beta blockers
•CHF
•Post-MI
•SVT
•Subaortic stenosis
"I use beta blockers all the time, just not for uncomplicated hypertension."
Heartbeat – June 2003
Continental Divide
Including beta blockers
JNC 7 was designed to be a document that could be looked at prospectively or retrospectively for events associated with hypertension
"Was it reasonable to include beta blockers across the entire spectrum of early to late disease? . . . The answer clearly is yes."
Izzo
Heartbeat – June 2003
Continental Divide
Beta-blocker heterogeneity
Messerli
The beta blockers are one of the most heterogeneous drug classes around
•Carvedilol, celiprolol, etc may be more beneficial in the uncomplicated hypertensive patient
No outcome data yet
Heartbeat – June 2003
Continental Divide
ALLHAT and the elderly
Opie
ALLHAT is seen by many as the main study influencing JNC 7
ALLHAT studied a population aged mean 67 years, with five-year follow-up
Earlier studies have found diuretics ineffective in whites under the age of 60
•Did that age factor get discussed in JNC 7?
Heartbeat – June 2003
Continental Divide
ALLHAT influence
JNC 7 is not just an ALLHAT study, although it did have many ALLHAT investigators on the committee
JNC 7 used the totality of evidence•Clinical trials•Expert opinion•No evidence-ranking system •Sifted through as much evidence as
we could
Izzo
Heartbeat – June 2003
Continental Divide
Age
Age is a trend that affects clinical judgment
Diuretics affect systolic pressure better in an older person than in a younger
"But those are the kinds of things that we feel expert clinicians should be able to interpret and use on their own."
65 + one day doesn't automatically mean diuretic Izzo
Heartbeat – June 2003
Continental Divide
Population vision
Opie
JNC 7 comes out right up front that hypertension is a graded effect, starting from 115/75, with a gradually increasing risk
This breadth of approach was missing from the European guidelines
Heartbeat – June 2003
Continental Divide
Minimal benefits
Messerli
Meta-analysis has shown increased risk for 130/80 compared with 115/75, but no one has shown reducing the former to the latter actually helps
"The benefits are probably so small that it's awfully hard to convince anybody that lowering the blood pressure within the normotensive range actually did reduce morbidity and mortality."
Heartbeat – June 2003
Continental Divide
Best guess
Lacked intervention trial data for “prehypertensive” patients
Vigorous lifestyle modification recommended for "prehypertensive" patients
Framingham study showed lower blood pressure was at any age, the lower it stayed throughout your life
Izzo
Heartbeat – June 2003
Continental Divide
Responsibility of the patient
Best available information is to emphasize a nonpharmacological approach
The concept of "prehypertension" is an attempt to put responsibility on patients to take better care of themselves
It was an attempt to avoid using drugs unnecessarily
Izzo
Heartbeat – June 2003
Continental Divide
Fat city
Messerli
The US is the fattest nation on Earth
New Orleans is the fattest city in the US
"Here the attitude is that everybody needs to have a good time first and all other considerations are second. So I'm not really happy about that prehypertensive term for this reason, because it doesn't motivate my patients to do anything."
Heartbeat – June 2003
Continental Divide
Action steps
Other terms don't motivate patients either
European guidelines use classifications so narrow that normal variation can change a patient's classification
JNC 7 made every 20/10 increase double the risk and that becomes an action step shared by the physician and the patient
Izzo
Heartbeat – June 2003
Continental Divide
High-risk categories
European guidelines use a higher-risk category for systolic >180, JNC 7 does not
There are no specifics in treatment approach that change between systolic 180 and 160
JNC 7 tried to focus on vigorous early treatment, and higher categories make people complacent at the lower levels
Izzo
Heartbeat – June 2003
Continental Divide
Clarity of message
Opie
JNC 7 delivers its message very clearly
"Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator."
-JNC 7
The phrase "thiazide-type diuretics should be used" may not be the best phrasing
Heartbeat – June 2003
Continental Divide
Specialists vs general practitioners
European guidelines offer a wonderful balance of approaches, but it is a document for specialists
Busy US primary care providers don't have time to read and use highly detailed documents
"We knew we had to have a punched-up, short document to get their attention at all."
Izzo
Heartbeat – June 2003
Continental Divide
Box summaries
Messerli
European guidelines have 16 boxes summarizing major guidelines and position statements
"The physician who is more interested can, at his or her leisure, just expand and read on, or not."
Heartbeat – June 2003
Continental Divide
Aggressive early treatment
Opie
JNC 7 more intense and aggressive in its approach than European guidelines
Diuretic therapy is known to take up to three months to be fully effective
Diuretic therapy is salt dependent
"Can you really reconcile the desire to get there quickly with blood-pressure reduction with the prime use of a diuretic?"
Heartbeat – June 2003
Continental Divide
Algorithm for treatment
Not at goal blood pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease)
Lifestyle modifications
Initial drug choices
Without compelling indications
Stage 1 hypertension(SBP 140–159 or DBP 90–99 mm Hg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.
Stage 2 hypertension (SBP >160 or DBP >100 mm Hg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)
With compelling indications
Drugs for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.
Not at goal blood pressure
Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist
JNC 7
Heartbeat – June 2003
Continental Divide
Doctors don't titrate
Early effective doses make sense because doctors don't titrate drugs
"I'd rather have them use effective doses relatively early in the game than hope that they will titrate when we know they don't do it."
Izzo
Heartbeat – June 2003
Continental Divide
European aggression
Messerli
Not that much of a difference between the US and European approach on early treatment
ACE inhibitors and ARBs also have a lead-in time and are salt-dependent
"I'm not so sure whether it would, in this regard, make a big difference whether you actually start on a diuretic or you start on an ACE inhibitor or calcium antagonist."
Heartbeat – June 2003
Continental Divide
Summary: Izzo
The fundamental differences are stylistic
JNC 7 is a digest but one with enough breadth to handle typical problems seen by physicians treating hypertension
The unsaid theme is "lower is better"
Put more pressure on patients and physicians to do a more vigorous job of managing hypertension Izzo
Heartbeat – June 2003
Continental Divide
Summary: Izzo
The diuretic recommendation is more interpretive than some would say
"Most" can mean 51% or 99% should be on a diuretic--there should be lots of combination therapy used
"These are only guidelines and they're not intended to replace educated physician judgment, just to be sign posts along the way."
Izzo
Heartbeat – June 2003
Continental Divide
Summary: Messerli
Major issues with JNC 7
•Lack of distinct guidelines for metabolic syndrome
•All drug classes considered equally compelling in diabetic patient
Messerli
Heartbeat – June 2003
Continental Divide
Summary: Messerli
"The responsible physician's judgment is paramount in managing patients, and I only hope that this judgment is also paramount in reading the guidelines."
"And this is true for the European guidelines as well as the American guidelines."
Messerli
Heartbeat – June 2003
Continental Divide
Lionel Opie MDProfessor and Head, Heart Research InstituteUniversity of Cape TownCape Town, South Africa
Franz Messerli MDAssociate Section Head, HypertensionOchsner Clinic FoundationNew Orleans, LA
Joe Izzo MDProfessor of MedicineKaleida Health/Millard Fillmore HospitalBuffalo, NY
Continental Divide:Hypertension guidelines –US vs Europe