How Recent Hypertension Trials are going to change our Practice

Roadmap

Hypertension Causes of hypertension Profile of an ideal hypertensive Recent Guidelines for the Management of Hypertension Lessons from clinical trials Concluding Remarks

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Hypertension

Hypertension is the most common public health problem in developed countries

Called Silent Killer

No cure is available, but prevention and management decrease the incidence of hypertension and disease sequelae.

Definition: Persistently high arterial blood pressure, defined as systolic blood pressure above 140 mm Hg and/or diastolic blood pressure above 90 mm Hg

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Hypertension: The Silent Killer

Facts & Figures 50 million Americans & 1 billion worldwide affected

Most common primary care diagnosis (35 million visits annually)

Normotensive at age 55 have 90% lifetime risk of Hypertension

Continuous & consistent relationship with CVD Between ages 40-70, starting from 115/75 CVD risk doubles with each increment of 20/10

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Causes of hypertension

1- Primary hypertension (90 – 95%) - Essential hypertension

2- Secondary hypertension (5 – 10%) - Renal diseases - Endocrine disease

- Steroid excess: Conn's syndrome, Cushing's syndrome

- Growth hormone excess: Acromegaly - Catecholamine excess: Phaeochromocytoma

- Vascular causes : Renal artery stenosis, Atheroma, Coarctation of the aorta

- Drugs: Sympathomimetic, Estrogens, Cyclosporine, NSAIDs

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Peripheral vascular disease

Morbidity

Disability

Renal disease

CAD

CHFLVHStroke

Hypertension

National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.

Hypertension: A Significant CV and Renal Disease Risk Factor

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Global Risk Profile and Hypertension

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Trends in Awareness, Treatment & Control of Hypertension

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ULTIMATE GOAL OF ANTIHYPERTENSIVE THERAPY

PROLONGED SURVIVAL

BLOODPRESSURE REDUCTION

PREVENTIONOF

COMPLICATIONS

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PROFILE OF AN IDEAL ANTIHYPERTENSIVE

Scientific rationale and selective mechanism of action

Simple pharmacokinetic profile

Consistent blood pressure reduction

Outstanding safety and tolerability

Superior to existing therapies

Easy to use in special populations

Effects beyond blood pressure reduction

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Recent Guidelines for the Management of Hypertension

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The correct Approach to Hypertension

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1. NICE Guidelines (2006)

Measuring Blood Pressure

Hypertension according to nice is a BP of greater than 140/90 (QOF > 150/90)

Need at least two further readings of > 140/90 in order to diagnose hypertension

Take these measurements one month apart or earlier if severe hypertension

In diabetics hypertension BP> 130/80

www.nice.org.uk

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2. British Hypertension Society (2003)

Category Systolic blood

pressure (mmHg)

Diastolic blood

pressure

(mmHg) Optimal blood pressure <120 <80

Normal blood pressure <130 <85

High-normal blood pressure 130-139 85-89

Grade 1 Hypertension (mild) 140-159 90-99

Grade 2 Hypertension (moderate) 160-179 100-109

Grade 3 Hypertension (severe) >180 >110

Isolated Systolic Hypertension (Grade 1) 140-159 <90

Isolated Systolic Hypertension (Grade 2) >160 <90

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3. Canadian Hypertension Education Program (CHEP) (2007)

Key CHEP messages for the management of hypertension

• Assess blood pressure at all appropriate visits. • Almost one half of those with blood pressure 130-139/85-

89 will develop hypertension within 2 years. They require annual reassessment.

• Assess global cardiovascular risk in all hypertensive patients.

• Lifestyle modification is the cornerstone for the prevention and management of hypertension and CVD.

2007 Canadian Hypertension Education Program Recommendations

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4. JNC VII Guidelines (2003)

Management & Classification

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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Life Style Modifications

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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Clinical Trial & Guideline basis for compelling Indications for individual Drug Classes

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Algorithm for Treatment Hypertension

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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5. INDIAN HYPERTENSION GUIDELINES-II

Classification

www.apiindia.org/hypertensionguidelines

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Ambulatory blood pressure monitoring

www.apiindia.org/hypertensionguidelines

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Hypertension trials change clinical practice?

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Hypertension trials change clinical practice?

Three large international trials will really improve our understanding of hypertension management.

International Verapamil SR/Trandolapril Study (INVEST).

Antihypertensive and lipid lowering Treatment to prevent heart attack trial (ALLHAT).

Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial.

The 3 trials combined included 81,649 patients over a period of 7 year from 18 countries (North & South America, Europe, Australia and Asia)

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ALLHAT TRIAL

ALLHAT is a randomized, double blind, active controlled clinical trial in the United States, Canada, Puerto Rico and US Virgin Islands.

This study compares effectiveness of newer antihypertensive agents versus traditional antihypertensive with diuretics.

42,448 patients from 625 sites were enrolled into of four treatment groups.

Patients were randomized into chlorthalidone, amlodipine, lisinopril and doxazosin treatment groups in a 1.7:1:1:1 ratio.

SBP treatment goal was <140 mmHg, DBP goal was <90 mmHg.

The primary outcomes of treatment included non fatal myocardial infarction (MI) and cardiovascular death.

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CONVINCE TRIAL

16,602 patients enrolled from centres around the world.

Subjects were randomized in a 1:1 ration to receive extended release verapamil or the investigators choice of atenolol or hydrochlorothiazide.

Goal for study was <140 mmHg for SBP and <90 mmHg for DBP.

The primary outcome of the study included fatal and non fatal stroke, fatal and non fatal MI and other cardiovascular death.

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INVEST TRIAL

22,599 patients with hypertension and CAD from around the world were enrolled.

Trial compares the effectiveness of verapamil SR versus atenolol, with or without trandolapril and/or hydrochlorothiazide.

Treatment arms in a 1:1 ratio.

First clinical trial in hypertension to employ JNC VI guidelines as treatment goals.

SBP goal is <140 mmHg and the DBP goal is <90 mmHg for patients who do not have diabetes or renal disease; SBP goal <130 mmHg and the DBP goal is <85 mmHg for patients who have diabetes and/or renal disease.

Primary outcomes of this trial are nonfatal MI, non fatal stroke or death.

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Table: Comparison of baselines characteristic of the enrolled populations in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the Controlled ONset Verapamil Investigation of Cardiovascular Endpoints(CONVINCE) trial , and the International VErapamil SR/trandolapril Study(INVEST)

ALLHAT(%)

CONVINCE(%)

INVEST(%)

Female 47 56 52

Black 36 7 14

Hispanic 19 7 37

Documented CAD 26 8 100

Diabetes 36 20 27

Mean age 67 66 66

Mean BMI 30 a 29

Prior smoking history 40 23 46

Dyslipidemia b 31 53

Prior Stroke c 5 5

Prior MI c 8 32

a Not reportedb Reported mean total cholesterol = 5.6mmol/Lc Reported combined prior MI/stroke = 23%

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Table: Comparison of treatment goals and strategies associated with the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the Controlled ONset Verapamil Investigation of Cardiovascular Endpoints(CONVINCE) trial , and the International VErapamil SR/trandolapril Study(INVEST)

ALLHAT CONVINCE INVEST

SBP goal (mmHg)DBP goal (mmHg)Treatment strategies

<140<90

Step 1 – double blind, randomized:

Chlorthalidone vs Amlodipine vs Lisinopril vs

doxazosinStep 2 – open label

Reserpine or clonidine or

atenololStep 3- open label:hydralazine

<140<90

Step 1 – double blind,

randomized; controlled

onset extended release

verapamil vs physician

directed choice of HCTZ or

atenololStep 2 and beyond-

includes increase in

either dose or number of

agents necessary to achieve BP

control

<140 or < 130 for diabetes and renal dysfunction <90 or <85 for diabetes & renal dysfunctionStep 1 – open label, randomized: Verapamil SR vs

atenolol Both strategies also contain trandolapril and/or HCTZ

which may be prescribed as step 1 as necessary based on patient characteristics

Step 2 and beyond –includes an increase in either dose or number of study agents or the addition of nonstudy agents necessary to achieve Bp control

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Management strategies

The JNC guidelines provided initial management strategies for patients according to risk group and blood pressure level.

Because patients in risk group A were at minimal risk, only lifestyle modifications were indicated for the group. However patients in risk group C (max risk) who had a blood pressure of 130-139/85-89 mmHg were advised drug therapy as an initial intervention in addition to lifestyle modification.

Immediate drug intervention was advised for all patients with a blood pressure level <160/100mmHg, regardless or risk group.

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Guidelines of the Second European Task Force

European guidelines included lifestyle modification and a blood pressure level of <140/90 mmHg as primary goals. In addition, goals included a total cholesterol level of 5mmol/l (193 mg/dl) and a low-density lipoprotein (LDL) level of 3 mmol/l (116mg/dl).

Risk stratification in the European guidelines was based on co morbidities and target organ damage, and is very similar to but not exactly the same as the JNC guidelines.

Like JNC, the European guidelines suggest treatment of elevated blood pressure based on the severity of hypertension and cardiac risk, and the degree of target organ damage.

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Bars represent the percentage of hypertensives on treatment as measured in various studies. Arrows represent published clinical trial findings.

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Lessons from clinical trials

Regarding the management of hypertension, many lessons have been gained from clinical trials.

The Hypertension Optical Treatment (HOT) study showed that a DBP level of 80 mmHg is associated with decreased cardiovascular events and mortality.

The Nordic Diltiazem (NORDIL) study demonstrated that calcium antagonists were as effective as diuretics and beta blockers in lowering blood pressure and reducing cardiovascular events and mortality.

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Need for Awareness for Clinicians

Cardiologists and primary care physicians have a responsibility to be educated about hypertension and coronary artery disease.

In many instances, cardiologists are the primary care physicians for patients with coronary disease. Specialists do not see a large proportion and CHD: therefore, primary care physicians have never been must be educated.

Data showed that 41% or primary care physicians have never been heard of JNC.

In addition, patients must be educated about lifestyle about lifestyle modifications and the significance of elevated blood pressure.

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Concluding Remarks

In recent years there has been increased emphasis on making clinical decisions based on evidence from the medical literature.

Prior to 1995, 10%-20% of clinical decisions were cited as evidence- based (i.e., founded on clinical trial-tested therapies cited in the medical literature).

In 1998, Michaud et al, did a study on the proportion of "major therapeutic interventions justified by published evidence." They found >60% of the medical decisions studied were rooted in trial evidence.

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Concluding Remarks

Almost 50% were shown to be significantly superior to the treatments against which they were being compared.

"A treatment that has been around for a long time, even if trials have shown it to be of no value, will fade from favor more slowly than one still in its infancy."[1] However, therapies do change. According to Thornton,[15] it is ultimately the "interpretation and dissemination of data that influences changes in clinical decision making."

Clinical trials are now generally accepted as the "gold standard" for establishing practice standards.

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References

Pepine CJ, Hanberg-Thurmond E, Marks RG, Conlon M, Cooper-DeHoff R, Volkers p, Zellig P: Rationale and design of the INternationak VErapamil and SR/trandolapril Study (INVEST): An Internet-based randomized trial in coronary artery disease patients with hypertension. J Am Coll cardiol 1998;32:1228-1237

2. Grimm Rh Jr. Margolis KL, Papademetriou VV, Cushman WC, Ford CE, Betterncourt J, Alderman MH, Basile JN, Black HR, De Quattro VV, Eckfeldt J, Hawkins CM, Perry HM jr. Proschan M: Baseline characteristics of participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 2001;37:19-27

3. Black HR, Elliott WJ, Neaton JD, Granditis G, Grambsch P, Grimm RH Jr, Hansson L, Lacoucciere Y, Muller J, Sleight P, Weber MA, White MB, Williams G, Wittes J, Zanchetti A, Fakouhi TD, Anders RJ. Baselines characteristics and early blood pressure control in the CONVINCE trial. Hypertension 2001;37:12-18

4. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-2446

http://www.medscape.com/viewarticle/407692_4

Thornton H. Clinical trials, consensus conferences, and clinical practice. Lancet. 1999;354(9183):1037. Thornton H. Clinical trials, consensus conferences, and clinical practice. Lancet. 1999;354(9183):1037.

Meinert CL. Clinical Trials. New York, NY: Oxford University Press, Inc; 1986.

Stykowski PA, D'Agostino RB, Belanger AJ, et al. Secular trends in long-term sustained hypertension, long-term treatment, and cardiovascular mortality: the Framingham study 1950 to 1990. Circulation. 1996;93(4):697-703.

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References

Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328:914-921.

Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1982;248:1465-1477.

For NHANES I and NHANES III: The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication Number 98-4080, 1997.

The Systolic Hypertension in the Elderly Program (SHEP) Study Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265:3255-3264.

Liebson PR, Grandits GA, Dianzumba S, et al. Coronary heart disease/hypertrophy: comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the treatment of mild hypertension study (TOMHS). Circulation. 1995;91(3):698-706.

ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996;9(4Pt 1):342-360.

HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principle results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118): 1755-1762.

Michaud G, McGowan JL, van der Jagt R, et al. Are therapeutic decisions supported by evidence from health care research? Arch Intern Med. 1998;158:1665-1668.

Thank You

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