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Continental Divide Continental Divide: Hypertension guidelines-US vs Europe Lionel Opie MD Professor and Head, Heart Research Institute University of Cape Town Cape Town, South Africa Franz Messerli MD Associate Section Head, Hypertension Ochsner Clinic Foundation New Orleans, LA Joseph Izzo MD Vice Chair, Department of Medicine SUNY at Buffalo Buffalo, NY 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 BP Classification SBP 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 DBP mm Hg JNC 7 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? Heartbeat – June 2003 Izzo 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" Heartbeat – June 2003 European guidelines Continental Divide Problems with "prehypertensive" 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 Messerli Continental Divide Integrated risk factors 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 Messerli Continental Divide Data beyond randomized trials European guidelines acknowledge eventbased 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 Messerli Continental Divide Socioeconomic factors 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 Opie 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 Heartbeat – June 2003 Izzo 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 "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 Messerli Continental Divide ALLHAT: De novo diabetes Chlorthalidone Lisinopril Amlodipine 12.0 Events (%) 10.0 8.0 6.0 4.0 2.0 0.0 Heartbeat – June 2003 JAMA 2002; 288:2981-2997 Continental Divide Treating the metabolic syndrome "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 Messerli Continental Divide Indications for individual drug classes 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 JNC 7 Continental Divide ALLHAT: Primary end point Chlorthalidone Lisinopril Amlodipine 12.0 Events (%) 10.0 8.0 6.0 4.0 2.0 0.0 Heartbeat – June 2003 JAMA 2002; 288:2981-2997 Continental Divide Trial basis for treatment decisions 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 Heartbeat – June 2003 Continental Divide ALLHAT: Fasting glucose levels Chlorthalidone Lisinopril Amlodipine Fasting glucose >126 mg/dL (%) 35 30 25 20 15 10 5 0 Heartbeat – June 2003 Baseline 2 years 4 years JAMA 2002; 288:2981-2997 Continental Divide Indications for individual drug classes Compelling Indication HF Diuretic BB * Post-MI ACEI * * * * High coronary disease risk * * * Diabetes * * * Heartbeat – June 2003 ARB CCB * AldoANT * * * * * 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/dL ACE inhibitor: 121.5 mg/dL New-onset diabetes: Thiazide: 11.6% ACE inhibitor: 8.1% Heartbeat – June 2003 Izzo 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 Heartbeat – June 2003 Izzo Continental Divide Inappropriate wording "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 Messerli Continental Divide Treating diabetic patients 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 Messerli Continental Divide Thiazide diuretic definitions JNC 7 says "thiazide-type diuretics" • What do you understand by low-dose thiazide? • Are thiazide diuretics the same as chlorthalidone? Heartbeat – June 2003 Opie 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 Heartbeat – June 2003 Izzo 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." Heartbeat – June 2003 Izzo 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 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 Messerli Continental Divide Not enough data 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 Opie 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 Heartbeat – June 2003 Izzo 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 dosedependent side effects "We do not have very good clinical pharmacology to back up any of these recommendations that we're making." Heartbeat – June 2003 Izzo Continental Divide Head to head 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 Messerli Continental Divide Beta blockers 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 Opie 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 Heartbeat – June 2003 Izzo Continental Divide Elderly 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 Opie Continental Divide Uncomplicated hypertension 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 Messerli Continental Divide Beta blockers in cardiac disease 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 Messerli Continental Divide Good indications for beta blockers 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 Messerli 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." Heartbeat – June 2003 Izzo Continental Divide Beta-blocker heterogeneity 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 Messerli Continental Divide ALLHAT and the elderly 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 Opie 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 Heartbeat – June 2003 Izzo 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 Heartbeat – June 2003 Izzo Continental Divide Population vision 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 Opie Continental Divide Minimal benefits 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 Messerli 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 Heartbeat – June 2003 Izzo 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 Heartbeat – June 2003 Izzo Continental Divide Fat city 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 Messerli 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 Heartbeat – June 2003 Izzo 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 Heartbeat – June 2003 Izzo Continental Divide Clarity of message 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 Opie 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." Heartbeat – June 2003 Izzo Continental Divide Box summaries 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 Messerli Continental Divide Aggressive early treatment 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?" Opie Heartbeat – June 2003 Continental Divide Algorithm for treatment Lifestyle modifications Not at goal blood pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease) Initial drug choices Without compelling indications Stage 1 hypertension Stage 2 hypertension (SBP 140–159 or DBP 90–99 mm Hg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. (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 Heartbeat – June 2003 Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist JNC 7 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." Heartbeat – June 2003 Izzo Continental Divide European aggression 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." Messerli 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 Heartbeat – June 2003 Izzo 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." Heartbeat – June 2003 Izzo 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 Heartbeat – June 2003 Messerli 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." Heartbeat – June 2003 Messerli Continental Divide Continental Divide: Hypertension guidelines – US vs Europe Lionel Opie MD Professor and Head, Heart Research Institute University of Cape Town Cape Town, South Africa Franz Messerli MD Associate Section Head, Hypertension Ochsner Clinic Foundation New Orleans, LA Joe Izzo MD Professor of Medicine Kaleida Health/Millard Fillmore Hospital Buffalo, NY Heartbeat – June 2003