Hypertension: New Concepts, Guidelines, and Clinical Management Nathan D. Wong, PhD, FACC Associate Professor and Director Heart Disease Prevention Program Division of Cardiology, Department of Medicine College of Medicine, University of California, Irvine
Prevalence of Cardiovascular Disease
10 20 30 40 50 60 High BP CAD CHF Stroke Other 50,000,000 12,200,000 4,600,000 4,400,000 2,800,000 Prevalence (millions) BP=blood pressure, CAD=coronary artery disease, CHF=congestive heart failure
Estimated Number of Persons With Cardiovascular Disease in the US
American Heart Association ® . 2000 Heart and Stroke Statistical Update. 1999.
Age Distribution of Hypertensives in US Population (NHANES III and the 1991 Census) 3.7 9.5 13 21.3 23.7 19.2 9.6 Hypertensives Within Age Group (%) Franklin SS. J Hypertension. 1999;17(suppl 5):S29-S36. Age Groups (y) 47.4 million hypertensives 26.0% of US population 26% 74% 0 5 10 15 20 25 30 18-29 30-39 40-49 50-59 60-69 70-79 80+
<40 40-49 50-59 60-69 70-79 80+ Age (y) 17% 16% 16% 20% 20% 11% Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by Age Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874 . Frequency of hypertension subtypes in all untreated hypertensives (%) ISH (SBP 140 mm Hg and DBP <90 mm Hg) SDH (SBP 140 mm Hg and DBP 90 mm Hg) IDH (SBP <140 mm Hg and DBP 90 mm Hg) 0 20 40 60 80 100
Hypertension: A Significant CV and Renal Disease Risk Factor Peripheral vascular disease Morbidity Disability Renal disease CAD CHF LVH Stroke Hypertension National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.
Benefits of Lowering BP Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50%
Preventable CHD Events from Control of Hypertension in US Adults (Wong et al., Am Heart J 2003; 145: 888-95) PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%
Preventable CHD Events from Control of Hypertension in US Adults (Wong et al., Am Heart J 2003; 145: 888-95) (cont.)
The greatest impact (absolute numbers) from control of hypertension occurs in men, older persons, and those with isolated systolic hypertension
The greatest proportion of preventable CHD events from control of hypertension occurs in women
Optimal control of blood pressure could prevent more than one third of CHD events in men and more than half of CHD events in women
BP Control Rates Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74 Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6. 34 27 29 10 Control 59 54 55 31 Treatment 70 68 73 51 Awareness 1999–2000 II (Phase 2) 1991–94 II (Phase 1) 1988–91 II 1976–80 National Health and Nutrition Examination Survey, Percent
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) National Heart, Lung, and Blood Institute National High Blood Pressure Education Program U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute
Blood Pressure Classification <80 and <120 Normal 80–89 or 120–139 Prehypertension 90–99 or 140–159 Stage 1 Hypertension > 100 or > 160 Stage 2 Hypertension DBP mmHg SBP mmHg BP Classification
For persons over age 50, SBP is a more important than DBP as CVD risk factor
Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.
Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.
Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD.
New Features and Key Messages
4-Year Progression To Hypertension: The Framingham Heart Study (<120/80 mm Hg) (130/85 mm Hg) (130-139/85-89 mm Hg) Vasan, et al. Lancet 2001;358:1682-86 Participants age 36 and older
Impact of High-Normal BP on Risk of Major CV Events* in Men * Defined as death due to CV disease; recognized myocardial infarction (MI), stroke, or congestive heart failure (CHF). Adapted from Vasan RS. N Engl J Med. 2001;345:1291-1297. Cumulative Incidence (%) of Major CV Events Time (y) Optimal BP (<120/80 mm Hg) Normal BP (120-129/80-84 mm Hg) High-normal BP (130-139/85-89 mm Hg) 16 12 10 8 6 4 2 0 14 0 2 4 6 8 10 12
HOT Study: Significant Benefit From Intensive Treatment in the Diabetic Subgroup Hansson L et al. Lancet. 1998;351:1755-1762. 0 5 10 15 20 25 90 85 80 Major cardiovascular events/1,000 patient-years p =0.005 for trend mm Hg Target Diastolic Blood Pressure
SBP-Associated Risks: MRFIT Adapted from Neaton JD et al. Arch Intern Med . 1992;152:56-64 . SBP versus DBP in Risk of CHD Mortality Diastolic BP (mm Hg) Systolic BP (mm Hg) CHD Death Rate 100+ 90–99 80–89 75–79 70–74 <70 <120 120–139 140–159 160+ 48.3 20.6 10.3 11.8 8.8 8.5 9.2 23.8 16.9 13.9 12.8 12.6 11.8 31.0 25.5 24.6 25.3 25.2 24.9 37.4 34.7 43.8 38.1 80.6
Disease Relative Risk
Kidney failure (ESRD) 2.8
Heart failure 1.5
Peripheral vascular disease 1.8
Myocardial infarction* =1.6
Coronary artery disease 1.5
Elevated SBP Alone Is Associated With Increased Risk of Cardiovascular and Renal Disease ESRD = end-stage renal disease; SBP 165 mm Hg. *Men only. Adapted from Kannel WB. Am J Hypertens . 2000;13:3S-10S; Perry HM Jr et al. Hypertension. 1995;25(part 1):587-594; Klag MJ et al. N Engl J Med . 1996;334:13-18; Nielsen WB et al. Ugeskr Laeger . 1996;158:3779-3783; Neaton JD et al. Arch Intern Med . 1992;152:56-64.
Lowering SBP Benefits Older Patients
Clinical trials document importance of controlling elevated SBP to prevent cardiovascular disease
SHEP (Systolic Hypertension in the Elderly Program)
Syst-Eur (Systolic Hypertension in Europe)
Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264; Staessen JA et al. Lancet . 1997;350:757-764.
SHEP: Outcomes * P =.0003 vs placebo. Adapted from SHEP Cooperative Research Group. JAMA . 1991;265:3255-3264. Risk Reduction Risk Reduction (%) 0 – 10 – 20 – 30 – 40 – 50 – 36* Total Mortality – 13 Stroke
Systolic Hypertension in Europe (Syst-Eur)
Objective: To determine whether antihypertensive treatment reduces cardiovascular complications in older patients with elevated SBP
Patients: 4695 patients, 60 years of age, with SBP 160–219 mm Hg and DBP <95 mm Hg
Treatments: Nitrendipine (10–40 mg/day) with possible addition or substitution of:
Enalapril (5–20 mg/day)
Hydrochlorothiazide (12.5–25 mg/day)
Follow-up: 2 years (median)
Endpoint: Total stroke Myocardial infarction
Adapted from Staessen JA et al. Lancet. 1997;350:757-764.
Syst-Eur: Outcomes * P =.003; † P =.03; ‡ P =.12; § P <.001. Adapted from Staessen JA et al. Lancet . 1997;350:757-764 . Percent Reduction 0 – 5 – 10 – 15 – 20 – 25 – 30 – 35 – 40 – 45 – 42* Heart Failure Stroke All Cardiac Endpoints All Fatal/Nonfatal Cardiac Endpoints MI – 26 † – 29 ‡ – 30 ‡ – 31 § Risk Reduction
Increase in pulse pressure (PP) indicates greater stiffness in large conduit arteries, primarily the thoracic aorta.
PP , therefore, is a surrogate measure of dynamic, cyclic stress during systole.
PP may be a better marker of increased CV risk than either systolic BP or diastolic BP alone in older persons.
Prevalence of Selected Risk Factors in US Adults with the Metabolic Syndrome (without Diabetes) (Wong et al., Am J Cardiol 2003, in press)
Estimated Proportion of CHD Events Preventable by Control of Blood Pressure, HDL-C, LDL-C, and All 3 Factors to “Optimal” Levels in Persons with the Metabolic Syndrome (Wong et al., Am J Cardiol 2003, in press) ** * * p<0.05, ** p<0.01 compared to men
Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic
42,418 high-risk hypertensive patients ≥ 55 years
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Years to CHD Event 0 1 2 3 4 5 6 7 Cumulative CHD Event Rate 0 .04 .08 .12 .16 .2 0.81 0.99 (0.91-1.08) L/C 0.65 0.98 (0.90-1.07) A/C p value RR (95% CI) ALLHAT
Cumulative Event Rates for Stroke by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Cumulative Stroke Rate Years to Stroke 0 1 2 3 4 5 6 7 0 .02 .04 .06 .08 .1 0.02 1.15 (1.02-1.30) L/C 0.28 0.93 (0.81-1.06) A/C p value RR (95% CI) ALLHAT
Cumulative CHF Rate Years to HF 0 1 2 3 4 5 6 7 0 .03 .06 .09 .12 .15 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril <.001 1.19 (1.07-1.31) L/C <.001 1.38 (1.25-1.52) A/C p value HR (95% CI) ALLHAT
Overall Conclusions Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy. ALLHAT
JNC-VII New Features and Key Messages (Continued)
Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.
Certain high-risk conditions are compelling indications for other drug classes.
Most patients will require two or more antihypertensive drugs to achieve goal BP.
If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.
JNC-VII New Features and Key Messages (Continued)
The most effective therapy prescribed by the careful clinician will control HTN only if patients are motivated.
Motivation improves when patients have positive experiences with, and trust in, the clinician.
Empathy builds trust and is a potent motivator.
The responsible physician’s judgment remains paramount.
Evaluation of patients with documented HTN has three objectives:
Assess lifestyle and identify other CV risk factors or concomitant disorders that affects prognosis and guides treatment.
Reveal identifiable causes of high BP.
Assess the presence or absence of target organ damage and CVD.
BP Measurement Techniques Provides information on response to therapy. May help improve adherence to therapy and evaluate “white-coat” HTN. Self-measurement Indicated for evaluation of “white-coat” HTN. Absence of 10–20% BP decrease during sleep may indicate increased CVD risk. Ambulatory BP monitoring Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm. In-office Brief Description Method
CVD Risk Factors
Obesity* (BMI > 30 kg/m 2 )
Microalbuminuria or estimated GFR <60 ml/min
Age (older than 55 for men, 65 for women)
Family history of premature CVD
(men under age 55 or women under age 65)
*Components of the metabolic syndrome.
JNC VI: BP Risk Stratification
Risk Group A
No CV risk factors
No diabetes, target-organ damage, or clinical CVD
Risk Group B
At least one other risk factor: age >60, male gender or postmenopausal status, dyslipidemia, smoking, +FH
(No diabetes, target-organ damage, or clinical CVD)
Risk Group C
Diabetes or target-organ damage or clinical CVD with or without other risk factors
JNC VI. Arch Intern Med 1997;157:2413.
Target Organ Damage
Left ventricular hypertrophy
Angina or prior myocardial infarction
Prior coronary revascularization
Stroke or transient ischemic attack
Chronic kidney disease
Peripheral arterial disease
Blood glucose, and hematocrit
Serum potassium, creatinine, or the corresponding estimated GFR, and calcium
Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides
Measurement of urinary albumin excretion or albumin/creatinine ratio
More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved
Lifestyle Modification Approximate SBP reduction (range) Modification 5–20 mmHg/10 kg weight loss Weight reduction 8–14 mmHg Adopt DASH eating plan 2–8 mmHg Dietary sodium reduction 4–9 mmHg Physical activity 2–4 mmHg Moderation of alcohol consumption
Lose weight if overweight
Limit alcohol intake
Increase aerobic physical activity
Reduce sodium intake
Maintain adequate intake of potassium
Maintain adequate intake of calcium and magnesium
Reduce dietary saturated fat and cholesterol
For Prevention and Management For Overall and Cardiovascular Health
Dietary Approaches to Stop Hypertension (DASH)
Diet high in fruits and vegetables and low-fat dairy products lowers blood pressure (11 mmHg SBP/ 5 mmHg DBP lower than traditional US diet), including more than a sodium-restricted diet
Recommends 7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy products, 2 or less meat, poultry, and fish.
NEJM 1997; 366: 1117-24.
Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease ) Initial Drug Choices Lifestyle Modifications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Stage 2 Hypertension (SBP > 160 or DBP > 100 m mHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140 –159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.
Classification and Management of BP for adults *Treatment determined by highest BP category. † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡ Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. Two-drug combination for most † (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Yes or > 100 > 160 Stage 2 Hypertension Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Yes or 90–99 140–159 Stage 1 Hypertension Drug(s) for compelling indications. ‡ No antihypertensive drug indicated. Yes or 80–89 120–139 Prehypertension Encourage <80 <120 & Normal With compelling indications Without compelling indication Initial drug therapy Lifestyle modification DBP* mmHg SBP* mmHg BP classification
Followup and Monitoring
Patients should return for followup and adjustment of medications until the BP goal is reached.
More frequent visits for stage 2 HTN or with complicating comorbid conditions.
Serum potassium and creatinine monitored 1–2 times per year.
Followup and Monitoring (continued)
After BP at goal and stable, followup visits at 3- to 6-month intervals.
Comorbidities, such as heart failure, associated diseases, such as diabetes, and the need for laboratory tests influence the frequency of visits.
Indication for treatment, except immediately after ischemic cerebral infarction.
Coronary artery disease
Benefits of therapy well established.
Left ventricular hypertrophy
Antihypertensive agents (except direct vasodilators) indicated.
Reduced weight and decreased sodium intake beneficial.
Cardiovascular Diseases (continued)
ACE inhibitors, especially with digoxin or diuretics, shown to prevent subsequent heart failure.
Peripheral arterial disease
Limited or no data available.
Relative Risk of CV Events and Mortality: CCBs vs Diuretics or Beta Blockers CCBs, calcium channel blockers. CHD, coronary heart disease. * Includes INSIGHT, NICS-EH, STOP-2, NORDIL, and VHAS. Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk. Adapted from Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet . 2000;356:1955-1964. Stroke 456 529 0.87 (0.77-0.98) CHD 567 510 1.12 (1.00-1.26) Heart Failure 278 250 1.12 (0.95-1.33) Major CV Events 1,251 1,234 1.02 (0.95-1.10) CV Death 425 405 1.05 (0.92-1.20) Total Mortality 776 776 1.01 (0.92-1.11) Relative Risk Favors CCBs Favors diuretics or beta blockers CCBs (n=11,685) Diuretics or Beta Blockers (n=11,769) 0.5 1.0 2.0 No. of Events* Relative Risk (95% CI)
HOPE: Risk Reduction of CV Events Associated with ACEI (RAS Inhibition) Treatment Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med . 2000;342:145-153. -22 ( P <.001) MI, Stroke, CV Death (primary end point) -26 ( P <.001) CV Death -20 ( P <.001) MI -32 ( P <.001) Stroke -16 ( P =.005) All-cause Death -35 -30 -25 -20 -15 -10 -5 0 Risk Reduction (%)
Relative Risk of CV Events and Mortality: ACE Inhibitors vs Diuretics or Beta Blockers CHD, coronary heart disease. * Includes STOP-2, UKPDS-HDS, and CAPPP. Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk. Adapted from Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet . 2000;356:1955-1964. Stroke 425 402 1.05 (0.92-1.19) CHD 423 420 1.00 (0.88-1.14) Heart Failure 223 250 0.92 (0.77-1.09) Major CV Events 1,018 1,004 1.00 (0.93-1.08) CV Death 350 348 1.00 (0.87-1.15) Total Mortality 639 618 1.03 (0.93-1.14) Relative Risk Favors ACE inhibitors Favors diuretics or beta blockers No. of Events* ACE Inhibitors (n=8,097) Diuretics or Beta Blockers (n=8,064) 0.5 1.0 2.0 Relative Risk (95% CI)
Reversal of LV Hypertrophy By Antihypertensive Treatment Schmieder RE et al. JAMA. 1996;275:1507-1513. Change in LV mass index (%) Diuretics -blockers Calcium channel blockers ACE inhibitors p <.01 p <.01 7% 6% 9% 13% 0 -5 -10 -15 -20 -25
Regression of LV Hypertrophy Predicts Prognosis LV, left ventricular. Nonregressors defined as baseline and follow-up left ventricular mass index (LVMI) >125 g/m 2 ; regressors defined as baseline LVMI >125 g/m 2 and follow-up LVMI <125 g/m 2 . Adapted from Verdecchia P et al. Circulation. 1998;97:48-54. Probability of event-free survival (%) Rate of events (per 100 patient-yrs) Time to event (wk) P =.002 Regressors (n=285) Nonregressors (n=145) Regressors (n=52) Nonregressors (n=50) 0 100 200 300 400 500 100 90 80 70 0 60 50 7 6 5 4 1 3 2 0
Irbesartan and Atenolol in Hypertension and LVH Study Design Single-blind Placebo Irbesartan 150-300 mg Atenolol 50-100 mg Addition of HCTZ 12.5-25 mg if SeDBP 90 mm Hg Addition of Felodipine 5-10 mg if SeDBP 90 mm Hg Wk: -4 0 12 24 48 * BP, echocardiography, neurohormone measurements. Malmqvist K et al. J Hypertens. 2001;19:1167-1176. * Double Blind * * *
Irbesartan vs Atenolol in Hypertension and LVH: SeDBP Reduction -20 -15 -10 -5 0 12 wk 24 wk 48 wk % reduction in SeDBP Irbesartan Atenolol * * † * * * * * p <.001 vs baseline. † p <.028 irbesartan vs atenolol. Malmqvist K et al. J Hypertens. 2001;19:1167-1176.
Irbesartan vs Atenolol in Hypertension and LVH: LVMI Reduction -18 -16 -14 -12 -10 -8 -6 -4 -2 0 % change in LVMI (g/m 2 ) * p <.001 vs baseline; † p =.024 irbesartan vs atenolol. Malmqvist K et al. J Hypertens. 2001;19:1167-1176. Irbesartan Atenolol 12 wk * 24 wk * * 48 wk * * †
LIFE: Inclusion Criteria
Age 55-80 years
Previously treated or untreated hypertension
Systolic BP 160-200 mmHg or
Diastolic BP 95-115 mmHg
Adapted from Dahl ö f B et al. Am J Hypertens. 1997;10:705 -13 .
LIFE: Dosing * Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers. Adapted from Dahlöf B et al. Am J Hypertens. 1997;10:705-713. Titration to target blood pressure: <140 / <90 mmHg Placebo Run-in Losartan 50 mg Atenolol 50 mg Losartan 50 mg + HCTZ 12.5 mg Losartan 100 mg + HCTZ 12.5 mg Losartan 100 mg + HCTZ 12.5-25 mg + others* Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others* Average follow up 4.7 years
Losartan Atenolol (n=4,605) (n=4,588) RR (%) p -value
Primary composite † 508 588 -13 .021
CV mortality 204 234 -11 .21
Stroke 2 32 309 -25 .001
MI 198 188 +7 .49
Total mortality 383 431 -10 .13
New onset DM ‡ 241 319 -25 <.001
Adjusted* * For degree of LVH and Framingham risk score at randomization † Number of patients with a first primary event ‡ In patients without diabetes at randomization (losartan, n=4,019; atenolol, n=3,979) Adapted from B Dahl ö f et al. Lancet. 2002;359:995-1003.
Valsartan Heart Failure Trial (Val-HeFT)
Study Characteristics :
5,010 total patients randomized with NYHA class II, III, or IV HF
Two groups: valsartan (target dose 160 mg BID) plus standard therapy vs placebo plus standard therapy
Mean duration of follow-up: 23 months (range 0-38)
Two primary end points:
Combined mortality and morbidity (morbidity defined as cardiac arrest with resuscitation, hospitalization for HF, or administration of IV inotropic or vasodilator drugs for > 4 hours without hospitalization)
Overall mortality was similar in the two groups
13% RRR ( p =.009) in combined end point
Predominantly because of a 27% decrease in hospitalization for HF in the valsartan group
Valsartan had a favorable effect in patients receiving neither an ACE inhibitor nor a beta-blocker
Valsartan had a favorable effect in patients receiving an ACE inhibitor or a beta blocker
Valsartan demonstrated a statistically non-significant trend towards an adverse outcome in patients receiving an ACE inhibitor and a beta blocker
Web site www.nhlbi.nih.gov/
DASH Fact Sheet
Your Guide to Lowering Blood Pressure
Drug therapy should begin along with lifestyle modifications to reduce blood pressure to < 130/85 mm Hg.
ACE inhibitors, -blockers, calcium antagonists, and low-dose diuretics are preferred.
Insulin resistance or high peripheral insulin levels may cause hypertension, which can be treated with lifestyle changes, insulin-sensitizing agents, vasodilating antihypertensive drugs, and lipid-lowering agents.
Hypertension may result from renal disease that reduces functioning nephrons.
Evidence shows a clear relationship between high blood pressure and end-stage renal disease.
Blood pressure should be controlled to < 130/85 mm Hg or lower (< 125/75 mm Hg) in patients with proteinuria in excess of 1 gram per 24 hours.
ACE inhibitors work well to control blood pressure and slow progression of renal failure.
ADA Guidelines on Management of Diabetic Nephropathy
Hypertensive Type 2 Diabetic Patients*
ARBs are the initial agents of choice
Type 1 Diabetics with or without hypertension*
ACEIs are the initial agents of choice
If one class is not tolerated the other should be substituted
* With microalbuminuria and clinical proteinuria. Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.
MRFIT: Association of Systolic BP and Cardiovascular Death in Type 2 Diabetes < 120 120–139 140–159 160–179 180–199 200 Systolic blood pressure (mm Hg) Cardiovascular mortality rate/10,000 person-yr Nondiabetic Diabetic Stamler J et al. Diabetes Care. 1993;16:434-444. 250 225 200 175 150 125 100 75 50 0 25
Veterans Administration Hypertension and Screening Clinics 15-Year ESRD Rates and Risk Ratios by Baseline Systolic Blood Pressure SBP (mm Hg) Risk Ratio < 140 > 140 but < 151 > 151 but < 165 > 165 but < 180 > 180 1.00 1.00 1.08 2.07 5.62 Number of screenees: 11,912 (5,730 black; 6,182 white) Source: Perry HM, et al. Hypertension. 1995;25:587-594
Veterans Administration Hypertension and Screening Clinics 15-Year ESRD Rates and Risk Ratios by Baseline Diastolic Blood Pressure DBP (mm Hg) Risk Ratio < 94 > 94 but < 100 > 100 but < 106 > 106 but < 118 > 118 1.00 1.05 0.89 1.54 4.18 Number of screenees: 11,912 (5,730 black; 6,182 white) Source: Perry HM, et al. Hypertension. 1995;25:587-594
United Kingdom Prospective Diabetes Study (UKPDS): Results
Tight blood pressure control* with captopril- or atenolol-based therapy reduces risk of Risk reduction p -value
Any diabetes-related endpoints 24% 0.005
Diabetes-related deaths 32% 0.019
Stroke 44% 0.013
Microvascular endpoints 37% 0.009
* Mean blood pressure achieved: 144/82 vs 154/87 mm Hg. UK Prospective Diabetes Study Group 38. BMJ. 1998;317:703-713. UK Prospective Diabetes Study Group 33. Lancet. 1998;352:837-853.
Diabetic Nephropathy Burden of Illness
Approximately 40% of all new cases of ESRD in the U.S. are due to diabetes 1
Type 2 diabetes accounts for most cases of diabetic nephropathy 2,3
Prevalence of nephropathy 57% after 25 years of type 2 diabetes 4
In U.S. alone, total annual spending for ESRD > $15 billion 1
Cost/patient-year higher for diabetic ESRD ($51,000) than nondiabetic ESRD ($39,000) 5
1. USRDS Coordinating Center. USRDS 1999 Annual Data Report. The Kidney Epidemiology and Cost Center of the University of Michigan; 1999. NIH Contract no. NO1-DK-3-2202. 2. American Diabetes Association. Diabetes Care. 2001;24 (supp 1):S69-72. 3. Ritz E, et al. Am J Kidney Dis. 1996;27:167-194. 4. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. 5. Ruggenenti P et al. J Am Soc Nephrol. 1998;9:2336-2343.
Diabetic Nephropathy Burden of Illness (continued)
1.5-2.5x greater mortality among diabetics with ESRD than nondiabetics 1
< 20% of diabetics with ESRD survive 5 years after initiation of dialysis 1
Cardiovascular complications the most common cause of death 2,3
1. Koch M et al. Diabetologia. 1993;36:1113-1117. 2. Bakris GL. Diabetes Res Clin Pract. 1998;39:S35-S42. 3. Grundy SM et al. Circulation. 1999;100:1134-1146.
Correlation Between MAP & Renal Function GFR, glomerular filtration rate; HTN, hypertension; MAP, mean arterial pressure. Adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. GFR Decline (mL/min/y) MAP (mm Hg) 95 98 101 107 104 110 113 116 119 r=0.69; P <.05 Untreated HTN 130/85 140/90 0 -2 -4 -6 -8 -10 -12 -14
Microalbuminuria as a Risk Factor for Death in Type 2 Diabetes UAC, urinary albumin concentration. Adapted from Schmitz A et al. Diabetes Med. 1988;5:126-134. Years after Diagnosis Survival UAC 15 g/mL UAC 16-40 g/mL UAC 41-200 g/mL 0.0 0.4 1.0 0.8 0.6 0.2 0 5 10 2 1 3 4 7 6 8 9 11
Proteinuria & Risk of CV Mortality,Stroke, & CHD Events in Type 2 Diabetes CHD, coronary heart disease; UPC, urinary protein concentration. * Defined as CHD death or nonfatal MI. Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039. A: UPC <150 mg/L B: UPC 150-300 mg/L C: UPC >300 mg/L 1.0 0.9 0.8 0.7 0.6 0.5 0 0 10 20 30 40 50 60 70 80 90 Stroke CHD Events* P <.001 for trends Incidence (%) Reduction in Survival due to CV Mortality Months A B C P -values: Overall <.001 A vs B =.013 A vs C <.001 B vs C <.001 0 10 20 30 40
Risk Reduction of Diabetes-Related End Points with Tight BP Control * Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or hypoglycemia. † Fatal or nonfatal. ‡ Retinopathy requiring photocoagulation, vitreous hemorrhage and fatal or nonfatal renal failure. Mean BP achieved with captopril- or atenolol-based therapy: 144/82 mm Hg (tight BP control) vs 154/87 mm Hg (less tight BP control). Adapted from UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. Risk Reduction (%) Diabetes-related Mortality* Stroke † Microvascular End Points ‡ Myocardial Infarction 32 44 37 21 0 10 20 30 40 50
HOT: Significant Benefit From Intensive Antihypertensive Treatment in Diabetes * Defined as fatal and nonfatal MI, fatal and nonfatal stroke, and all other CV death. Adapted from Hansson L et al. Lancet. 1998;351:1755-1762. 0 5 10 15 20 25 90 85 80 Major CV Events*/1000 Patient-yrs in Hypertensive Patients with Diabetes P =.005 for trend Target DBP (mm Hg)
Effect of ACE Inhibition on Nephropathy in Type 1 Diabetes * P=.006 vs placebo. Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462. Progression to Death, Dialysis, or Transplant (%) Captopril Placebo Follow-up (y) * 0 1 2 3 4 0 10 20 30 40
IRMA 2: Blood Pressure Response SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. At the end of 2-year follow-up, 56% of patients in the control group, 45% in the irbesartan 150-mg group, and 43% in the irbesartan 300-mg group were receiving concomitant antihypertensive agents. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878. Control SeDBP* Irbesartan 150 mg SeDBP* Irbesartan 300 mg SeDBP* Control SeSBP* Irbesartan 150 mg SeSBP* Irbesartan 300 mg SeSBP* Mean SeSBP and SeDBP (mm Hg) Months 0 3 6 9 12 15 18 21 24 27 0 70 130 160 80 90 100 110 120 140 150
IRMA 2 Primary Endpoint Development of Overt Proteinuria Subjects (%) Control (n=201) 150 mg (n=195) 300 mg (n=194) Irbesartan 9.7 5.2 14.9 RRR=39% P =0.08 RRR=70% P<0.001 Parving H-H, et al. N Engl J Med 2001;345:870-878. 14 18 16 12 10 8 6 4 2 0
IDNT: Systolic BP, Mean Arterial Pressure, & Diastolic BP Response Control defined as placebo. Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups, and 3.3 concomitant agents in the control group. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Irbesartan Amlodipine Control Follow-up Visit (mo) SBP MAP DBP BP (mm Hg) 0 6 12 18 24 30 36 42 48 54 80 100 120 140 160
IDNT Primary Endpoint: Time to Doubling of Serum Creatinine, ESRD, or Death Subjects (%) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) 60 Irbesartan Amlodipine Control Lewis EJ et al. N Engl J Med 2001;345:851-860. RRR 20% P =0.02 P =NS RRR 23% P =0.006 0 10 20 30 40 50 60 70
IDNT & RENAAL: Study Design SeCr, serum creatinine; ESRD, end-stage renal disease. † Lewis EJ et al. N Engl J Med. 2001;345:851-860. ‡ Brenner BM et al. N Engl J Med. 2001;345:861-869. Patients: 1,715 HTN patients with type 2 1,513 HTN patients with diabetes & nephropathy type 2 diabetes & nephropathy Treatment arms: irbesartan, amlodipine, losartan, placebo placebo Target BP: 135/85 mm Hg 140/90 mm Hg Adjunctive therapy: Permitted except ARBs, Permitted including ACE inhibitors, or CCBs CCBs, except ARBs or ACE inhibitors Primary outcome: Composite of doubling of Composite of doubling of SeCr, ESRD, or death SeCr, ESRD, or death Secondary outcomes: CV events CV events Mean Follow-up: 2.6 years 3.4 years RENAAL ‡ IDNT †
IDNT and RENAAL Trial Results Doubling of Creat, 16 ( P =0.02) 20 ( P =0.02) 23 ( P =0.006) -4 ( P =0.69) ESRD, or death Doubling of Creat 25 ( P =0.006) 33 ( P =0.003) 37 ( P< 0.001) -6 ( P =0.60) ESRD 28 ( P =0.002) 23 ( P =0.07) 23 ( P =0.07) 0 ( P =0.99) Death -2 ( P =0.88) 8 ( P =0.57) -4 ( P =0.8) 12 ( P =0.4) CV Morbidity 10 (P=0.26) 9 (P=0.4) -3 (P=0.79) 12 (P=0.29) & Mortality Losartan vs control Irbesartan vs control Irbesartan vs amlodipine Amlodipine vs control RRR (%) Comparison of Major Endpoints RENAAL IDNT Lewis EJ et al. N Engl J Med 2001;345:851-860. Brenner B et al. N Engl J Med 2001;345:861-869.
In general, treatment similar for all demographic groups.
Socioeconomic factors and lifestyle important barriers to BP control.
Prevalence, severity of HTN increased in African Americans.
African Americans demonstrate somewhat reduced BP responses to monotherapy with BBs, ACEIs, or ARBs compared to diuretics or CCBs.
These differences usually eliminated by adding adequate doses of a diuretic.
Left Ventricular Hypertrophy
LVH is an independent risk factor that increases the risk of CVD.
Regression of LVH occurs with aggressive BP management: weight loss, sodium restriction, and treatment with all classes of drugs except the direct vasodilators hydralazine and minoxidil.
Peripheral Arterial Disease (PAD)
PAD is equivalent in risk to ischemic heart disease.
Any class of drugs can be used in most PAD patients.
Other risk factors should be managed aggressively.
Aspirin should be used.
Hypertension in Older Persons
More than two-thirds of people over 65 have HTN.
This population has the lowest rates of BP control.
Treatment, including those who with isolated systolic HTN, should follow same principles outlined for general care of HTN.
Lower initial drug doses may be indicated to avoid symptoms; standard doses and multiple drugs will be needed to reach BP targets .
Decrease in standing SBP >10 mmHg, when associated with dizziness/fainting, more frequent in older SBP patients with diabetes, taking diuretics, venodilators, and some psychotropic drugs.
BP in these individuals should be monitored in the upright position.
Avoid volume depletion and excessively rapid dose titration of drugs.
Dementia and cognitive impairment occur more commonly in people with HTN.
Reduced progression of cognitive impairment occurs with effective antihypertensive therapy.
Hypertension in Women
Oral contraceptives may increase BP, and BP should be checked regularly. In contrast, HRT does not raise BP.
Development of HTN—consider other forms of contraception.
Pregnant women with HTN should be followed carefully. Methyldopa, BBs, and vasodilators, preferred for the safety of the fetus. ACEI and ARBs contraindicated in pregnancy.
Strategies for Improving Adherence to Regimens
Clinician empathy increases patient trust, motivation, and adherence to therapy.
Physicians should consider their patients’ cultural beliefs and individual attitudes in formulating therapy.
Causes of Resistant Hypertension
Improper BP measurement
Excess sodium intake
Inadequate diuretic therapy
Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)
Over-the-counter ( OTC) drugs and herbal supplements
Excess alcohol intake
Identifiable causes of HTN
Public Health Challenges and Community Programs
Public health approaches (e.g. reducing calories, saturated fat, and salt in processed foods and increasing community/school opportunities for physical activity) can achieve a downward shift in the distribution of a population’s BP, thus potentially reducing morbidity, mortality, and the lifetime risk of an individual’s becoming hypertensive.
These public health approaches can provide an attractive opportunity to interrupt and prevent the continuing costly cycle of managing HTN and its complications.
Web site www.nhlbi.nih.gov/
For patients and the general public
“ Facts About the DASH Eating Plan” (Revised May 2003)
“ Your Guide to Lowering Blood Pressure”
For health professionals
Back-up Slides: Special Populations
Racial and ethnic groups
Children and adolescents
Potential Pathogenic Properties of Angiotensin II
Endothelial dysfunction with decreased release of nitric oxide
Coronary constriction via release of norepinephrine
Formation of oxygen-derived free radicals via NADH (nicotinamide adenine dinucleotide) oxidase
Promotion of inflammatory response and plaque instability
Promotion of low-density lipoprotein cholesterol uptake
Adapted from Opie and Gersh. Drugs for the Heart , 2001.
Potential Pathogenic Properties of Angiotensin II (continued)
Increased intraglomerular pressure
Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Decreased renal blood flow
Increased formation of aldosterone
Increased PAI-1 (plasminogen activator inhibitor-1) relative to tissue plasminogen factor
Adapted from Opie and Gersh . Drugs for the Heart , 2001.
Summary of Chapter 3 (continued)
Management strategies can improve adherence through the use of multidisciplinary teams.
The reductions in cardiovascular events demonstrated in randomized controlled trials have important implications for managed care organizations.
Management of hypertensive emergencies requires immediate action, whereas urgencies benefit from reducing blood pressure within a few hours.
A low dose of initial drug should be used, slowly titrating upward.
Optimal formulation should provide 24-hour efficacy with once-daily dose with at least 50% of peak effect remaining at end of 24 hours.
Combination therapies may provide additional efficacy with fewer adverse effects.
Classes of Antihypertensive Drugs
Angiotensin II receptor blockers
-adrenergic blockers and diuretics
ACE inhibitors and diuretics
Angiotensin II receptor antagonists and diuretics
Calcium antagonists and ACE inhibitors
Followup within 1 to 2 months after initiating therapy.
Recognize that high-risk patients often require high dose or combination therapies and shorter intervals between changes in medications.
Consider reasons for lack of responsiveness if blood pressure is uncontrolled after reaching full dose.
Consider reducing dose and number of agents after 1 year at or below goal.
Guidelines for Improving Adherence to Therapy
Be aware of signs of nonadherence.
Establish goal of therapy.
Encourage a positive attitude about achieving goals.
Educate patients about the disease and therapy.
Maintain contact with patients.
Encourage lifestyle modifications.
Keep care inexpensive and simple.
Guidelines for Improving Adherence to Therapy (continued)
Integrate therapy into daily routine.
Prescribe long-acting drugs.
Adjust therapy to minimize adverse effects.
Continue to add drugs systematically to meet goal.
Consider using nurse case management.
Utilize other health professionals.
Try a new approach if current regime is inadequate.
Racial and Ethnic Groups African Americans
Among the highest prevalence
Generally low prevalence
Lowest control rate in Mexican Americans
Asian and Pacific Islanders
May be more responsive to treatment than other groups
Similar prevalence to general population
High prevalence of diabetes and obesity
Clinical trials have not demonstrated significant differences between men and women in treatment response and outcomes.
Some women using oral contraceptives may have significant increases in blood pressure.
High blood pressure is not a contraindication to hormone replacement therapy.
Chronic hypertension is high blood pressure present before pregnancy or diagnosed before the 20th week of gestation.
Preeclampsia is increased blood pressure that occurs in pregnancy (generally after the 20th week) and is accompanied by edema, proteinuria, or both.
ACE inhibitors and angiotensin II receptor blockers are contraindicated for pregnant women.
Methyldopa is recommended for women diagnosed during pregnancy.
Antihypertensive Drugs Used in Pregnancy These agents* may be used with chronic hypertension (DBP > 100 mm Hg) or acute hypertension (DBP > 105 mm Hg). Central -agonists Methyldopa is the drug of choice. -blockers and - -blockers Atenolol, metoprolol, and labetalol appear safe and effective in late pregnancy. Calcium antagonists Potential synergism with magnesium sulfate may lead to precipitous hypotension. *Limited or no controlled trials in pregnant women.
Antihypertensive Drugs Used in Pregnancy (continued) These agents* may be used with chronic hypertension (DBP > 100 mm Hg) or acute hypertension (DBP > 105). Diuretics Diuretics are recommended for chronic hypertension if prescribed before gestation, but they are not recommended for preeclampsia. Direct vasodilators Hydralazine is the parenteral drug of choice based on its long history of safety and efficacy. *Limited or no controlled trials in pregnant women. ACE inhibitors and angiotensin II receptor blockers are contraindicated.
Hypertension is common.
SBP is a better predictor of events than DBP.
Pseudohypertension and “white-coat hypertension” may indicate a need for readings outside the office.
Primary hypertension is the most common cause, but common identifiable causes (e.g., renovascular hypertension) should be considered.
Older Persons (continued)
Therapy should begin with lifestyle modifications.
Starting doses for drug therapy should be lower than those used in younger adults.
Goal of therapy is the same (< 140/90 mm Hg), although an interim goal of SBP < 160 mm Hg may be necessary.
Combined Results of Five Randomized Trials of Antihypertensive Treatment in the Elderly Stroke 0 100 200 300 400 500 600 78 288 T T = Treatment C = Control = Fatal events 120 438 C CHD 208 346 T 279 438 C Vascular deaths Total numbers of individuals affected 383 T 494 C All other deaths 34% (6) 2P <0.0001 % (SD) reduction in odds 19% (7) 2P <0.05 23% (6) 2P <0.001 – 7% (8) 2P >0.5 344 362 T C
SHEP STOP-HTN MRC SYST-EUR (1991) (Dahlöf, 1991) (1992) (1997) Mean BP 170/77 195/102 185/91 174/85 at entry (mm Hg)
Effects of Therapy in Elderly Hypertensive Patients
IRMA 2: Study Design
590 patients with hypertension, type 2 diabetes, microalbuminuria (albumin excretion rate 20–200 µg/min), and normal renal function
Double-blind Treatment Up to 5 weeks Screening/Enrollment Irbesartan 150 mg* Irbesartan 300 mg* Follow-up: 2 years Placebo/Control group* * Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and dihydropyridine calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels. Parving H-H, et al. N Engl J Med 2001;345:870-878.
Mechanism of Action of Angiotensin II Receptor Antagonists Angiotensinogen Angiotensin I Angiotensin II AT 2 receptor AT 1 receptor Other AT receptors Bradykinin Inactive peptides Vasodilation Attenuate growth and disease progression ACE inhibitors Alternate pathways AIIRAs ? ?
IRMA 2 : Clinical Outcome Measures
Time to occurrence of overt proteinuria (AER > 200 g/min)
Change in AER
Regression to normoalbuminuria (AER < 20 g/min)
Change in creatinine clearance
Clotting factors and lipid profile
Parving H-H, et al. N Engl J Med 2001;345:870-878.
IDNT: Study Design
1,715 patients with hypertension, type 2 diabetes, and proteinuria 900 mg/day
Double-blind Treatment Up to 5 weeks Screening/Enrollment Placebo/Control group* Amlodipine* Minimum follow-up: approximately 2 years (average follow-up 2.6 years) Irbesartan* * Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels. Lewis EJ et al. N Engl J Med 2001;345:851-860.
IDNT Clinical Outcome Measures
Primary outcome is time to a composite endpoint consisting of:
Secondary outcome is time to a composite endpoint of fatal or nonfatal cardiovascular events
Lewis EJ et al. N Engl J Med 2001;345:851-860.
Potential Pathogenic Properties of Angiotensin II
Increased intraglomerular pressure
Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Decreased renal blood flow
Adapted from Opie and Gersh. Drugs for the Heart , 2001.
IRMA 2: Study Design Double-blind treatment 3 weeks Screening/enrollment Irbesartan 150 mg/d † Irbesartan 300 mg/d † Follow-up: 2 years Control †
590 patients with hypertension, type 2 diabetes, microalbuminuria, * and normal renal function
Control defined as placebo. * Defined as albumin excretion rate 20-200 µg/min. † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2: Clinical Outcome Measures
Time to occurrence of overt proteinuria (UAER >200 mg/min)
Change in UAER
Regression to normoalbuminuria (UAER <20 mg/min)
Change in creatinine clearance
UAER, urinary albumin excretion rate. Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2: Mean Baseline Characteristics N Age (y) Male (%) BMI (kg/m 2 ) BP (mm Hg) HbA 1c (%) SeCr (mg/dL) Irbesartan 150 mg/d 195 58 66 29.9 153/90 7.3 1.0 Irbesartan 300 mg/d 194 57 71 30.0 153/91 7.1 1.1 Control 201 58 69 30.3 153/90 7.1 1.0 UAER (µg/min) 58 53 55 Duration of diabetes (y) 9.5 9.2 10.4 Control defined as placebo. BMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbA 1c , glycosylated hemoglobin. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2 Primary End Point: Time to Overt Proteinuria RRR, relative risk reduction. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878. Follow-up (mo) Control (n=201)* Irbesartan 150 mg/d (n=195)* Irbesartan 300 mg/d (n=194)* RRR=39% P =.08 RRR=70% P <.001 Patients (%) 0 3 6 12 18 22 24 0 5 10 15 20
IRMA 2: Normalization * of UAER UAER, urinary albumin excretion rate. Control defined as placebo. * Normoalbuminuria defined as UAER of <20 mg/min. † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. Parving H-H et al. N Engl J Med. 2001;345:870-878. Control † (n=201) 150 mg/d † (n=195) 300 mg/d † (n=194) Irbesartan 24 34 21 P =.006 Patients (%) 35 45 40 30 25 20 15 10 5 0
IRMA 2: Adverse Events Cardiovascular events 18 (8.7) 1 14 (6.9) 2 9 (4.5) 1 Serious AE 47 (22.8) 1 32 (15.8) 2 30 (15.0) 2 Discontinuations due to AE 19 (9.2) 2 18 (8.9) 2 11 (5.5) 2 Control group* (n=201) Irbesartan 150 mg* (n=195) Irbesartan 300 mg* (n=194) No. of Adverse Events (%) Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. 1. Parving H-H, et al. N Engl J Med. 2001;345:870-878. 2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
IRMA 2: Summary
The renal benefits of irbesartan are independent of its BP-lowering effects 1
70% risk reduction in the progression from microalbuminuria to overt diabetic nephropathy with irbesartan 300 mg/d vs control (P<.001) 1
More frequent restoration of normoalbuminuria with irbesartan 300 mg/d vs control (P=.006) 1
Irbesartan is safe & well tolerated 2
Fewer nonfatal CV events, serious AEs, and discontinuations due to AEs in the irbesartan groups 2
AE, adverse event. 1. Parving H-H et al. N Engl J Med. 2001;345:870-878. 2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
IDNT: Study Design 1,715 patients with hypertension, type 2 diabetes, & proteinuria 900 mg/d Double-blind treatment Up to 5 weeks Screening/enrollment Control* Amlodipine* Minimum follow-up: approximately 2 years (average follow-up, 2.6 years) Irbesartan* Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to help achieve target BP. Lewis EJ et al. N Engl J Med. 2001;345:851-860.
IDNT: Clinical Outcome Measures
Primary outcome: time to composite end point of
Doubling of baseline SeCr
ESRD (dialysis, renal transplant, or SeCr ³6 mg/dL)
Death (all-cause mortality)
Secondary outcome: time to composite end point of
fatal or nonfatal CV events
SeCr, serum creatinine; ESRD, end-stage renal disease. Lewis EJ et al. N Engl J Med. 2001;345:851-860.
IDNT: Mean Baseline Demographics N Age (y) Male (%) Non-white (%) BMI (kg/m 2 ) History of CV disease (%) Retinopathy (%) Irbesartan 579 59 65 24 31.0 27 69 Amlodipine 567 59 63 31 30.9 30 64 Control 569 58 71 28 30.5 29 67 Control defined as placebo. BMI, body mass index. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Duration of diabetes (y) 15 14 15
IDNT: Baseline Exam & Laboratory Characteristics Irbesartan Amlodipine Control SBP (mm Hg)* 160 159 158 Control defined as placebo. SeCr, serum creatinine; HbA 1c , glycosylated hemoglobin. * Mean. † Median. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. DBP (mm Hg)* 87 87 87 SeCr (mg/dL)* 1.67 1.65 1.69 Urine protein (g/24 h) † 2.9 2.9 2.9 HbA 1c (%)* 8.1 8.2 8.2
IDNT Primary End Point: Time to Doubling of SeCr, ESRD, or Death Control defined as placebo. SeCr, serum creatinine; ESRD, end-stage renal disease; RRR, relative risk reduction. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Irbesartan (n=579) Amlodipine (n=565) Control (n=568) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) Patients (%) RRR=20% P =.02 P =NS RRR=23% P =.006 0 10 20 30 40 50 60 70
IDNT: Time to Doubling of SeCr Control defined as placebo. SeCr, serum creatinine; RRR, relative risk reduction. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Patients (%) Follow-up (mo) Irbesartan (n=579) Amlodipine (n=567) Control (n=569) RRR=33% P =.003 P =NS RRR=37% P <.001 0 6 12 18 24 30 36 42 48 54 0 10 20 30 40 50 60 70
IDNT Secondary End Point: CV Events * No significant differences between groups. Control defined as placebo. * Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in hospitalization, a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860. Control (n=569) Irbesartan (n=579) Amlodipine (n=567) 25.3 23.8 22.6 Patients (%) 0 10 20 30 5 15 25
IDNT: Adverse Events Early SeCr rise (n) 2 0 0 1 Discontinuations due to hyperkalemia [n (%)] 1 11 (1.9) 3 (0.5) 2 (0.4) Stopped study medicine [n (%)] 2 134 (23) 133 (23) 140 (25) SAEs/1000 days on drug (%) 2 2.0 2.5 2.3 Irbesartan Amlodipine Control No. of AEs AE, adverse event; SAE, serious adverse event. Control defined as placebo. 1. Lewis EJ et al. N Engl J Med. 2001;345:851-860. 2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
Irbesartan reduced the composite risk of progression of renal disease or total mortality, independent of its BP-lowering effects
20% RRR vs control (P=.02)
23% RRR vs amlodipine (P=.006)
No significant differences among groups for CV outcomes
Size and duration of study was insufficient to detect any differences
Irbesartan was generally safe and well tolerated
Lower rate of SAEs in the irbesartan group
SAE, serious adverse event; RRR, relative risk reduction. Lewis EJ et al. N Engl J Med. 2001;345:851-860.