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Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk. Joshua Furman, MD Staff Cardiologist Mount Sinai Medical Center Miami Beach, Florida. ?. Key Question. Which class of agents do you presently consider first-line treatment for patients

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Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

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  1. Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk Joshua Furman, MD Staff Cardiologist Mount Sinai Medical Center Miami Beach, Florida

  2. ? Key Question Which class of agents do you presently consider first-line treatment for patients with hypertension? • Diuretics • β-Blockers (BBs) • Calcium channel blockers (CCBs) • Angiotensin-converting enzyme inhibitors (ACEIs) • Angiotensin receptor blockers (ARBs) • All of the above Use your keypad to vote now!

  3. Faculty Disclosure • Dr Furman has no relevant financial relationships with any commercial interests to disclose.

  4. Learning Objectives • State the prevalence of hypertension and its role in the cardiovascular disease continuum • Formulate hypertension management according to risk stratification • Describe the importance of targeting improvement in vascular function in patients with hypertension

  5. Progression of Cardiovascular Disease: The Cardiovascular Continuum Myocardial infarction Myocardialischemia Ventricular dysfunction Sudden death Peripheral arterial disease Endothelialdysfunction and atherothrombosis Ventricular dilation and hypertrophy Stroke Congestive heart failure and death Hyperlipidemia,hypertension, diabetes, smoking, obesity, etc Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

  6. Development and Progression of Vascular Disease RISK FACTORS LDL BP Diabetes Smoking Oxidative Stress Endothelial Dysfunction andSmooth Muscle Activation NO •  Local Mediators •  Tissue ACE, AII EndothelinCatecholamines PAI-1, PlateletAggregation, Tissue Factor VCAM/ICAMCytokines Proteolysis Inflammation Growth Factors Cytokines Matrix Inflammation PlaqueRupture Vasoconstriction Thrombosis Vascular Lesionand Remodeling CLINICAL SEQUELAE Dzau V. Hypertension. 2001;37:1047-1052.

  7. Diastolic dysfunction LVH Death/ Sudden Death HF Systolic dysfunction ACS Atherothrombosis, left ventricular remodeling Subclinical left ventricular dysfunction Overt heart failure Progression From Hypertension to Heart Failure/Sudden Death Obesity Diabetes Hypertension Smoking Dyslipidemia Risk Factors Time ACS = acute coronary syndrome; HF = heart failure; LVH = left ventricular hypertrophy. Adapted from Vasan RS, Levy D. Arch Intern Med. 1996;156:1789-1796.

  8. JNC 7 Cardiovascular Risk Factors • Microalbuminuria or estimated GFR <60 mL/min • Age (men >55 yr; women >65 yr) • Family history of premature CVD • Hypertension • Cigarette smoking • Obesity (BMI ≥30 kg/m2) • Physical inactivity • Dyslipidemia • Diabetes mellitus Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  9. 100 90 80 70 60 50 40 30 20 10 0 In Nearly 2 Out of 3 Adults With Hypertension, Hypertension Is Still Not Controlled NHANES (1999-2000)‡ 30% 41% 66%! 70 59 US Population (%)* 34 Treated Controlled† Aware *Adults aged 18 to 74 years with hypertension. †Controlled = BP 140/90 mm Hg. ‡Data were computed (M. Wolz, unpublished data, 2003) from the NHLBI. Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  10. Patients With BP Controlled Worldwide <160/95 mm Hg <140/90 mm Hg Australia5 Canada2 USA1 Finland5 Spain5 22% 27% 20.5% 20% 19% France4 Germany5 England3 Scotland5 India5 6% 17.5% 24% 22.5% 9% >65 yr only 1. JNC VI. Arch Intern Med. 1997;157:2413-2446. 2. Joffres et al. Am J Hypertens. 1997;10:1097-1102. 3. Colhoun et al. J Hypertens. 1998;16:747-752. 4. Chamontin et al. Am J Hypertens. 1998;11(6 Pt 1):759-762. 5. Marques-Vidal et al. J Hum Hypertens. 1997;11:213-220. Adapted from G. Mancia

  11. 10-Year NCEP/Framingham Risk Scores for Fatal or Nonfatal CHD in Men* *A separate Framingham risk calculator exists for women. NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/.

  12. ? Key Question What percentage of patients with hypertension have 2 or more additional CV risk factors? • 20% • 30% • 40% • 50% • >50% Use your keypad to vote now!

  13. CV Risk Factor Clustering With Hypertension: Framingham Offspring, Aged 18 to 74 Years >50% of Hypertension Occurs in Presenceof 2 or More Risk Factors Men Women 1 RF 2 RFs 1 RF 2 RFs 25% 24% 26% 27% 20% 22% 19% 17% 8% 12% No Additional RFs No Additional RFs 3 RFs 3 RFs 4 or More RFs 4 or More RFs RF = risk factor. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

  14. Risk of CHD in Mild Hypertension by Intensity of Associated Risk Factors 40 42 36 30 21 10-Year Probability of Event (%) 24 18 14 10 12 6 4 6 0 Risk Factors SBP 150-160 mm Hg + + + + + + TC 240-262 mg/dL − + + + + + HDL-C 33-35 mg/dL − − + + + + Diabetes − − − + + + Cigarette smoking − − − − + + ECG-LVH − − − − − + Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

  15. JNC Reclassification of BP Based on Risk JNC 7 JNC VI Arch Intern Med. 1997;157:2413-2446; Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  16. Nonpharmacologic Interventionsand BP Reduction Low-SaltDiet Weight Loss(19.4 lb) Alcohol Reduction Exercise 0 1 2 3 BP Decrease(mm Hg) 4 5 6 SBP DBP 7 Adapted from: Stevens VJ et al. Ann Intern Med. 2001;134:1-11; Messerli FH et al. In: Griffin BP et al, eds. 2004. Manual of Cardiovascular Medicine. 2nd ed; Whelton SP et al. Ann Intern Med. 2002;136:493-503; Cutler JA et al. Am J Clin Nutr. 1997;65(suppl):643S-651S; Xin X et al. Hypertension. 2001;38:1112-1117; Whelton PK et al. JAMA. 1997;277:1624-1632.

  17. Study Design: TROPHY STUDY N = 809 Participants had prehypertension: SBP 130-139 mm Hg and DBP 89 mm Hg ORSBP 139 mm Hg and DBP 85-89 mm Hg n = 409 2 years candesartan + 2 years placebo n = 400 2 years placebo + 2 years placebo When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated • RESULTS • At 2 years, hypertension had developed in 154 participants in the placebo group and 53 in the candesartan group (RRR 66%, P <.001) • At 4 years, hypertension had developed in 240 participants in the placebo group and 208 in the candesartan group (RRR 15.6%, P <.007) TROPHY = Trial of Preventing Hypertension. Julius S, et al. N Engl J Med. 2006;354:1685-1697.

  18. TROPHY: Kaplan-Meier Curves of New Onset Clinical Hypertension 100 90 Candesartan Placebo 80 70 60 Cumulative Incidence (%) 50 40 30 20 10 0 0 1 2 3 4 Years in Study TROPHY = Trial of Preventing Hypertension. Julius S et al. N Engl J Med. 2006;354:1685-1697.

  19. Key Points for Optimal Hypertension Management <140/90 mm Hg <130/80 mm Hg in patients with diabetes or renal disease JNC 7BPGoals • JNC 7 recommends: • If SBP >20 mm Hg or DBP >10 mm Hg over goal, • consider initiating with 2-drug combination Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  20. Antihypertensive Medications: Mechanism of Action American Heart Association. December 11, 2006. Available at:http://www.americanheart.org/presenter.jhtml?identifier=3038158.

  21. JNC 7: Algorithm for Hypertension LIFESTYLE MODIFICATIONS Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease) INITIAL DRUG CHOICES With Compelling Indications Without Compelling Indications Stage 2 Hypertension 2-drug combos for most (usually thiazide-type diuretics and ACEI, or ARB, or BB, or CCB) Compelling Indications Other drugs (diuretic, ACEI, ARB, BB, CCB) as needed Stage 1 Hypertension Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB, or combo If not at goal BP, optimize dosages or add drugs until goal BP achieved; consider consultation with hypertension specialist Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  22. JNC 7 Highlights: Key Risk-Related Messages • Certain high-risk conditions are compelling indications for the initial use of specific antihypertensive drug classes Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  23. JNC 7: Compelling Indications for Antihypertensive Drug Classes Recommended Drugs AldoCompelling Indication Diuretic ACEI BB ARB CCB ANT Heart failure • • • •   • Post MI   • •     • High coronary disease risk • • •   •   Diabetes • • • • •   Chronic kidney disease   •  •     Recurrent stroke prevention •• Aldo ANT = aldosterone antagonist.Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

  24. Study Design: VALUE STUDY N = 15,245 Aged 50 years; With treated or untreated hypertension and high risk of cardiac events Step 1: valsartan 80 mg/dayStep 2: valsartan 160 mg/dayn = 7649 Step 1: amlodipine 5 mg/dayStep 2: amlodipine 10 mg/dayn = 7596 Both regimens included HCTZ in steps 3 and 4 Further drugs could be given to achieve BP control Randomized, double-blind, parallel group comparison • RESULTS • BP i with both treatments • Primary end point (composite of cardiac mortality and morbidity) occurred in valsartan 10.6% vs amlodipine 10.4%, HR 1.04 • Amlodipine effects were more pronounced in the early period • BP i4.0/2.1 mm Hg in the amlodipine group after 1 month VALUE = Valsartan Antihypertensive Long-term Use Evaluation. Julius S, et al. Lancet. 2004;363:2022-2031.

  25. Hazard Ratio Valsartan/Amlodipine Primary cardiac composite end point Cardiac mortality Cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.5 1 2.0 Favors Valsartan Favors Amlodipine VALUE: Hazard Ratios for Prespecified Analyses in Patients With Hypertension at High CV Risk • Patients had hypertension and were at high CV risk. • VALUE = Valsartan Antihypertensive Long-term Use Evaluation. • Julius S et al, for the VALUE trial group. Lancet. 2004;363:2022-2031.

  26. ? Key Question On average, how many drugs will a patient need to control hypertension? • 1 • 2 • 3 • 4 Use your keypad to vote now!

  27. ALLHAT 138 IDNT 138 RENAAL 141 UKPDS 144 ABCD 132 MDRD 132 HOT 138 AASK 128 * INVEST 131 1 2 3 4 Number of Antihypertensive Agents Needed to Achieve Systolic BP Control SBP achieved(mm Hg) Trial Number of BP Medications† *~50% patients required ≥3 medications. †Average per patient. Bakris et al. Am J Kidney Dis. 2000;36:646-661; ALLHAT. JAMA. 2002;288:2981-2997; Berl et al. Ann Intern Med. 2003;138:542-549; Bakris et al. Arch Intern Med. 2003;163:1555-1565; Wright et al. JAMA. 2002;288:2421-2431; Pepine et al. JAMA. 2003;290:2805-2816.

  28. Hypertension and Diabetes: Global CV Risk Reduction With Evidence-Based Intervention

  29. Diabetes ApproximatelyDoubles CVDRisk in Patients With Hypertension Adapted from Curb JD et al. JAMA. 1996;276:1886-1892; Hansson L et al. Lancet. 1998;351:1755-1762; Tuomilehto J et al. N Engl J Med. 1999:340:677-684.

  30. HOT Study: Fewer Major CV Events in Patients With Diabetes Randomized to Lower BP Goal P = .005 25 20 15 Stroke, MI, or CV Death (per 1000 patient-years) 10 5 0 80 90 85 Target DBP (mm Hg) Patients with hypertension and diabetes were given baseline felodipine, plus other agents in a 5-step regimen. Study N = 18,790; diabetes n = 1501. HOT = Hypertension Optimal Treatment; MI = myocardial infarction. Adapted from Hansson L et al, for the HOT Study Group. Lancet. 1998;351:1755-1762.

  31. UKPDS: Tight Glucose Versus Tight BP Control and CV Outcomes Tight glucose control (goal <6.0 mmol/L or 108 mg/dL) Tight BP control (average 144/82 mm Hg) Stroke Any Diabetic End Point DM Deaths Microvascular Complications 0 5% -10 10% 12% -20 Relative Risk Reduction (%) 24% * -30 32% 32% * 37% -40 * *P <.05 compared to tight glucose control 44% * -50 Patients had hypertension and Type 2 diabetes. N = 1148. UKPDS = United Kingdom Prospective Diabetes Study. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

  32. Antihypertensive Medications: Mechanism of Action American Heart Association. December 11, 2006. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3038158.

  33. The Renin-Angiotensin-Aldosterone System (RAAS) Angiotensinogen Kininogen Kallikrein Renin Bradykinin Angiotensin I ACE Angiotensin II Inactive Peptides • Blood Pressure • Vascular Proliferation • Oxidative Stress • Vascular Inflammation • Thrombogenesis • Aldosterone AT1 Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

  34. The Renin-Angiotensin-Aldosterone System (RAAS) Angiotensinogen Kininogen Renin Inhibitors  Kallikrein Renin Bradykinin Angiotensin I ACE Angiotensin II Inactive Peptides ARBs ¯Blood Pressure ¯Vascular Proliferation ¯Oxidative Stress ¯Vascular Inflammation • Thrombogenesis • Aldosterone AT1 Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

  35. The Renin-Angiotensin-Aldosterone System (RAAS) Angiotensinogen Kininogen Kallikrein Renin Bradykinin Angiotensin I ACE Angiotensin II Inactive Peptides ARBs  ARBs AT2 AT2 ¯Blood Pressure ¯Vascular Proliferation ¯Oxidative Stress ¯Vascular Inflammation • Thrombogenesis • Aldosterone AT1 Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

  36. Kininogen Kallikrein Nitric Oxide Bradykinin Kininase II  Inactive Peptides The Renin-Angiotensin-Aldosterone System (RAAS) Angiotensinogen Renin ACEIs Angiotensin I  ACE Angiotensin II ¯Blood Pressure ¯Vascular Proliferation ¯Oxidative Stress ¯Vascular Inflammation • Thrombogenesis • Aldosterone AT1 Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

  37. ACEI Trials in CAD Without HF: Primary Outcomes EUROPA: CV Death/MI/Cardiac Arrest HOPE: CV Death/MI/Stroke 14 20 Placebo Placebo 12 20% Risk Reduction HR = 0.80 (0.71–0.91) P = .0003 22% Risk Reduction HR = 0.78 (0.70–0.86) P <.001 15 10 Percent 8 Ramipril 10 mg 10 6 Perindopril 8 mg Percent 4 5 2 Time (years) Time (years) 0 0 0 1 2 3 4 5 0 1 2 3 4 QUIET: All CV Events PEACE: CV Death/MI/CABG/PCI 50 30 Quinapril 20 mg Placebo 4% Risk Increase HR = 1.04 (0.89–1.22) P = .6 40 25 4% Risk Reduction HR = 0.96 (0.88–1.06) P = .43 20 30 Percent Percent Trandolapril 4 mg 15 Placebo 20 10 10 Time (years) Time (years) 5 0 0 1 2 3 4 5 6 0 1 2 3 EUROPA Investigators. Lancet. 2003;362:782-788; HOPE Study Investigators. N Engl J Med. 2000;342:145-153; PEACE Trial Investigators. N Engl J Med. 2004;351:2058-2068; Pitt B, et al. Am J Cardiol. 2001;87:1058-1063.

  38. MICRO-HOPE, PERSUADE: CV Events in Patients With Diabetes MICRO-HOPE(n = 3577)CV death/MI/stroke PERSUADE(n = 1502)CV death/MI/cardiac arrest 25 25 Placebo Placebo 20 20 25% RRRP = .0004 19% RRRP = .13 15 15 Primary Outcome (%) Perindopril8 mg 10 10 Ramipril10 mg 5 5 0 0 5 0 1 2 3 4 5 0 1 2 3 4 Follow-Up (years) Follow-Up (years) MICRO-HOPE = Microalbuminuria, Cardiovascular, and Renal Outcomes (Heart Outcomes Prevention Evaluation); PERSUADE = Perindopril Substudy in Coronary Artery Disease and Diabetes. HOPE Study Investigators. Lancet. 2000;355:253-259; Daly CA et al. Eur Heart J. 2005;26:1369-1378.

  39. Impact of ACE Inhibitors on the Risk of Developing New-Onset Diabetes Mellitus RR = 0.66 (0.51-0.85) P <.001 5.4 New Diagnosis of Diabetes (%) 3.6 HOPE Trial: Ramipril 10 mg QD vs placebo; 9297 patients with vascular disease or diabetes plus 1 other CV risk factor, 4355 with hypertension; BP: baseline (139/79 mm Hg); 2 years: ramipril (135/76 mm Hg), placebo (138/78 mm Hg). Yusuf S et al. N Engl J Med. 2000;342:145-153.

  40. HOPE Study:Prevention of Diabetes With Ramipril 0.10 0.08 0.06 0.04 0.02 0 Placebo Ramipril Kaplan-Meier Rates 200 400 600 800 1000 1200 1400 1600 Days of Follow-Up (no diabetes at baseline) The occurrence of self-reported diabetes was reduced by 34% (95% CI, 15%-49%; P <.001) in the HOPE study. This effect was observed early and maintained consistently throughout the trial. HOPE Study Investigators. Lancet. 2000;355:253-259.

  41. MICRO-HOPE: Albuminuria in Patients With Diabetes 3.0 Placebo 2.5 Ramipril 2.0 P = .02 Mean Albumin/Creatinine Ratio (urine) 1.5 P = .001 1.0 0.5 0.0 1 0 4-5 2 3 Time (y) HOPE Study Investigators. Lancet. 2000;355:253-259.

  42. LIFE: Secondary End Points No. ofEvents Hazard Ratio (95% CI) End Points Total Mortality 814 Angina Pectoris 301 CHF 314 Revascularization 545 562 New-Onset Diabetes 0.5 1 2 Favors Losartan Favors Atenolol Dahlof B et al. Lancet. 2002;359:995-1003.

  43. LIFE: New-Onset Diabetes Intention-to-Treat 10 9 Atenolol 8 7 6 Proportion of Patients With First Event (%) Losartan 5 4 3 Adjusted Risk Reduction 25%, P = .001 Unadjusted Risk Reduction 25%, P = .001 2 1 0 0 6 12 18 24 30 36 42 48 54 60 66 Study Month Dahlof B et al. Lancet. 2002;359:995-1003.

  44. CV Pharmacotherapy: Impact on Newly Diagnosed Diabetes CAPPP STOP-2 HOPE ALLHAT ANBP2 LIFE SCOPE CHARM VALUE PEACE INVEST ALPINE ASCOT STOP-2 INSIGHT ALLHAT 0 10 20 Reduction of New Diabetes (%) 30 ACEI or ARB CA + ACEI or ARB 100 CA Randomized active treatment vs control (eg, placebo, diuretic, β-blocker  diuretic) CA = calcium antagonist.Pepine CJ, Cooper-DeHoff RM. J Am Coll Cardiol. 2004;44:509-512. Sever PS et al. Lancet. 2003;361:1149-1158.

  45. Multiple Mechanisms of ACEIin Cardiovascular Disease Blood pressure lowering Cardioprotective effects •  Preload and afterload •  LV mass •  Sympathetic stimulation •  Reperfusion injury • Improved myocardial remodeling Metabolic syndrome • Lipid neutral • Improved glucose metabolism • Increases adiponectin • Decreased insulin resistance Vasculoprotective effects • Direct antiatherogenic • Enhance endogenous fibrinolysis • Inhibit platelet aggregation • Antimigratory for mononuclear cells •  Matrix formation • Improve endothelial function • Antioxidant • Anti-inflammatory • Protection from plaque rupture • Improved arterial compliance and tone Modified from: Lonn E et al. Eur Heart J Suppl. 2003;5:A43-A48.

  46. Summary: The Case for Global CV Risk Management • CV disease remains the leading cause of death in both men and women in the United States • Data from the Framingham Heart Study have demonstrated clustering of risk factors—and that risk of death from CHD and stroke increases further with each added risk factor • Hypertension, a pivotal risk factor for CV disease, should prompt the search for the presence of additional risk factors • Recent clinical trials have provided evidence supporting a standard of care for the management of global CV risk

  47. Case Study

  48. Case Study: 55-Year-Old Man From India With Hypertension and Type 2 Diabetes • The patient is in for a checkup • History • Hypertension • Type 2 diabetes • Nonsmoker • No symptoms • Physical examination • BP: 148/96 mm Hg • Height: 64" • Weight: 178 lb • BMI: 30 kg/m2 • Waist circumference: 38" • Cardiac dysfunction status: normal ventricular function (LVEF 68%) • Laboratory values • Glucose: 148 mg/dL (fasting) • A1C: 8.8% • Creatinine: 1.5 mg/dL • Urinalysis: 1+ proteinuria • Lipid profile (mg/dL): • TC: 268; LDL-C: 168; HDL-C: 42; TG: 296 • Medications • HCTZ 25 mg/d • Glyburide 5 mg/d

  49. 10-Year NCEP/Framingham Risk Scores for Fatal or Nonfatal CHD in Men* *A separate Framingham risk calculator exists for women. NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/.

  50. ? Decision Point What is the JNC 7 goal for this patient who has hypertension, diabetes, and renal disease? • <120/80 mm Hg • <130/80 mm Hg • <140/80 mm Hg • <140/90 mm Hg Use your keypad to vote now!

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