Hypertension in Chronic Kidney Disease Vito M. Campese, MD

Transcription

1 Hypertension in Chronic Kidney Disease Vito M. Campese, MD Professor of Medicine, Physiology and Biophysics Division of Nephrology and Hypertension Center Co-Director USC/UKRO Kidney Research Center Keck School of Medicine, USC Los Angeles February, 26,

2 Case 1 (1) A 55-year-old female with c/c of increasing dyspnea on exertion. She smokes one pack of cigarettes per day but denies use of drugs or alcohol. Her mother was 77 years old and had type 2 diabetes mellitus and hypertension.

3 Case 1 (2) P.E.: weight 210 lbs; height 5' 5", BMI 35 gr/m 2. BP 184/116 supine and 172/108 standing. Her retina revealed marked arteriolar narrowing but no exudates or hemorrhages. No JVD or edema were noted. Heart examination: normal sinus rhythm; A2 greater than P2; and an S-4; no murmurs. EKG: LVH with strain pattern.

4 Case 1 (3) Urinalysis: 1+ protein, and UACR 240 mg/g ACR Serum K meq/l, creatinine 1.5 mg/dl, egfr 39 ml/min/m 2, fasting blood sugar 218 mg/dl and HbA1c 9.6%. Total cholesterol 280 mg/dl, LDL-cholesterol 180 mg/dl; HDLcholesterol 34 mg/dl, triglycerides 190 mg/dl.

5 Questions 1. What are the coronary risk factors and risk score?

6 Components of CVD Risk Stratification in Hypertensive Patients Major Risk Factors Smoking Dyslipidemia Diabetes Age >60 years old Gender (men and postmenopausal women) Family History of CVD Proteinuria/CKD Target Organ Damage Heart Disease LVH Angina or prior MI Prior coronary revascularization CHF Stroke or TIA Nephropathy Peripheral Arterial Disease Retinopathy Adapted from JNC-VI, Arch Intern Med. 1997;157: s

7 Coronary risk score 26%.

8 Summary of Studies on Nephropathy Progression SBP (mm Hg) GFR (ml/min/year) ~4.5 yrs r = 0.69; P < 0.05 Untreated HTN y/o, male, SCr=2 mg/dl AASK achieved BPs Updated from Bakris GL, et al. Am J Kidney Dis. 2000;36:

9 Case 1: Questions 1. What are the coronary risk factors and risk score? 2. Would you initiate 1 or 2 antihypertensive drugs?

10 Questions 1. What are the coronary risk factors and risk score? 2. Would you initiate 1 or 2 antihypertensive drugs? 3. What is your target BP?

11 Hypertension- JNC 8 Recommendation 1 Recommendation 1 Corollary Recommendation Corollary Recommendation Recommendation 2 Recommendation 2 Recommendation 3 Recommendation 3 Recommendation 4 Recommendation 4 In general population 60 years, initiate pharmacologic treatment to lower BP at SBP 150mmHg or DBP 90mmHg and to treat to a goal <150/90 (Grade A) In general population 60 years, initiate pharmacologic treatment to lower BP at SBP 150mmHg or DBP 90mmHg and to treat to a goal <150/90 (Grade A) In general population 60years, if pharmacologic treatment for high BP results in lower achieved SBP (eg <140mmHg) and treatment is well tolerated and without adverse effects on health or quality of life, treatment does not need to be adjusted. (Grade E) In general population 60years, if pharmacologic treatment for high BP results in lower achieved SBP (eg <140mmHg) and treatment is well tolerated and without adverse effects on health or quality of life, treatment does not need to be adjusted. (Grade E) In general population <60 years, initiate pharmacologic treatment to lower BP at DBP 90mmHg and treat to a goal DBP<90 (Grade E) In general population <60 years, initiate pharmacologic treatment to lower BP at DBP 90mmHg and treat to a goal DBP<90 (Grade E) In general population <60years, initiate pharmacologic treatment to lower BP at SBP 140mmHg and treat to a goal SBP<140. (Grade E) In general population <60years, initiate pharmacologic treatment to lower BP at SBP 140mmHg and treat to a goal SBP<140. (Grade E) In the population aged 18 years with chronic kidney disease (CKD), initiate pharmacologic treatment to lower BP at SBP 140 mm In Hg population or DBP mm years Hg and with treat CKD, to initiate goal SBP pharmacologic <140 mm Hg and goal treatment DBP <90 to mm lower Hg. BP (Grade at SBP 140mmHg E) or Recommendation 5 In 18 years with diabetes, initiate pharmacologic treatment to lower BP at SBP 140mg Hg or DBP 90mmHg and treat to goal <140/90 and goal DBP <90 mm Hg. (Grade E) In 18 years with diabetes, initiate pharmacologic treatment to lower BP at SBP 140mg Hg or DBP 90mmHg and treat to goal <140/90

12 Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus The ACCORD Study Group N Engl J Med Volume 362(17): April 29, 2010

13 Study Overview In a randomized trial, 4733 patients with type 2 diabetes mellitus who were at high risk for cardiovascular events received treatment aimed at a target systolic blood pressure of less than 120 mm Hg or less than 140 mm Hg The rates of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) were evaluated after a mean follow-up of 4.7 years

14 Blood Pressure at Baseline Standard Therapy (N=2371) Intensive therapy (N=2362) Systolic BP (mmhg) Diastolic BP (mmhg)

15 Mean Systolic Blood-Pressure Levels Study Visit The ACCORD Study Group. N Engl J Med 2010;362:

16 Kaplan-Meier Analyses of Selected Outcomes The ACCORD Study Group. N Engl J Med 2010;362:

17 Primary and Secondary Outcomes The ACCORD Study Group. N Engl J Med 2010;362:

18 The Accord Study Elevation in Sr. Creat. > 1.5 mg/dl Intensive Therapy 12.9 % 8.4% * Standard Therapy egfr 74.8 ml/min 80.6 ml/min* egfr < 30 ml/min 4.2% 2.2% *

19 Conclusion In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events

20 How low should blood pressure go? mm Hg The HOT Study (Hypertension Optimal Treatment)

21 Hypertension Optimal Treatment Trial: Cardiovascular Events in Diabetics Target DBP (mm Hg) No. of patients Achieved SBP (mm Hg) Achieved DBP (mm Hg) Major CV events (1000 patient-yrs) p< Target DBP (mm Hg) *Prospective, randomized, open with blinded end point (PROBE) evaluation. Treatment was felodipine-based with dose increments and concomitant therapy (ACE inhibitor or β-blocker ± diuretic) used to reach randomization target. In addition, half were also randomly assigned aspirin. Mean BP 105 mm Hg, each group. Achieved = mean of all BPs from 6 months of follow-up to end of study. BP=blood pressure, CV=cardiovascular,DBP=diastolic BP, SBP=systolic BP. Hansson L et al. Lancet. 1998;351:

22 AASK: African American Study of Kidney Disease and Hypertension Objective Design BP Levels Therapy To compare the effects of 2 levels of BP control and 3 different antihypertensive regimens on the progression of renal disease in nondiabetic African American hypertensive patients with chronic renal insufficiency Prospective, double-blind, randomized, multicenter trial Usual (MAP mm Hg) Low (MAP 92 mm Hg) Calcium antagonist (amlodipine), ACEI (ramipril), or β-blocker (metoprolol) for 4 to 6 y From Hall WD, et al. Ethn Dis. 1997;7(suppl):S1.

23 Mean Arterial Pressure During Follow-up 130 MAP (mm Hg) Low Goal (Achieved: 127/77) Usual Goal (Achieved: 140/85) Follow-up Month

24 Change in GFR (ml/min/1.73m2) from Baseline BP Goal Comparison 3 Mean (SE) Change in GFR P = 0.85 Overall rate of decline = 2 ml/min/yr Normal rate of decline in GFR 0.8 ml/min/yr Low Goal Usual Goal Follow-up Month

25 Composite Clinical Events: Declining GFR Event, ESRD or Death by BP Goal % with Events Low (Achieved: 127/77) Usual BP ((Achieved: 140/85) Low vs. Usual: RR=2%, (p=0.85) Follow-Up Time (Months) RR=Risk Reduction

26 A Randomized Trial of Intensive versus Standard Blood-Pressure Control The SPRINT Research Group N Engl J Med Volume 373(22): November 26, 2015

27 Study Overview Patients at increased cardiovascular risk but without diabetes were assigned to intensive treatment of systolic BP (target, <120 mm Hg) or standard treatment (target, <140 mm Hg). After a median of 3.26 years, the rate of cardiovascular events was significantly lower with intensive treatment.

28 Eligibility, Randomization, and Follow-up. The SPRINT Research Group. N Engl J Med DOI: /NEJMoa

29 Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial. The SPRINT Research Group. N Engl J Med DOI: /NEJMoa

30 Primary Outcome and Death from Any Cause. The SPRINT Research Group. N Engl J Med DOI: /NEJMoa

31 Forest Plot of Primary Outcome According to Subgroups. The SPRINT Research Group. N Engl J Med DOI: /NEJMoa

32 Primary and Secondary Outcomes and Renal Outcomes. The SPRINT Research Group. N Engl J Med DOI: /NEJMoa

33 Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events. The SPRINT Research Group. N Engl J Med DOI: /NEJMoa

34 Conclusions Among patients at high risk for CV events but without diabetes, targeting a systolic BP of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.

35 Differences between SPRINT and ACCORD ACCORD Study 4,733 All patients with NIDDM HTZ Mean age 62 Factorial design 11% in CV events, not significant 48% in stroke SPRINT Study 9,361 NIDDM excluded Chlortalidone Mean age 68 Open label design 25% in CV events (mostly driven by CHF), 27% in death No significant in stroke or MI 35

36 Estimated mean decline in the GFR from baseline in Study A. GFR declines are compared for patients in the usual and low protein diet groups in Study A. Estimated mean (±SEM) GFR declines from baseline (B) to selected follow-up times (F) are shown. Klahr S et al. N Engl J Med 1994;330: by American Society of Nephrology

37 Decline in the Glomerular Filtration Rate (GFR) According to Base-Line Urinary Protein Excretion and Blood-Pressure Group in Studies 1 and 2. Klahr S et al. N Engl J Med 1994;330:

38 Hypertensive patients with Diabetes and CKD Supine Standing Patient 1 140/90 140/90 Patient 2 140/90 120/75 Patient 3 140/90 160/100

39 Questions 1. What are the coronary risk factors and risk score? 2. Would you initiate 1 or 2 antihypertensive drugs? 3. What is your target BP? 4. What anti-hypertensive drugs?

40 Hypertension in CRF Mechanisms Sodium and volume excess The renin-angiotensin system Aldosterone Increased activity of the sympathetic nervous system Erythropoietin, cyclosporin, corticosteroids, NSAIDs Endothelium-derived vasoconstrictors and vasodilators Divalent Ions and PTH Atrial natriuretic peptide Structural changes of the arteries Pre-existent essential hypertension Miscellaneous: A-V fistula, Hypothyroidism, NSAIDs, etc.

41 Life-Style Modifications Reduce sodium intake Lose weight Limit alcohol intake Limit caffeine intake Increase aerobic exercise Increase intake of K + Reduce dietary saturated fat Stop smoking Adequate intake of dietary calcium and magnesium

42 RENAAL % with event P (+ CT) L (+ CT) Doubling of Serum Creatinine Risk Reduction: 25% P=0.006 P Months L % with event P (+ CT) L (+ CT) P=0.010 ESRD or Death Risk Reduction: 20% P Months L % with event P (+ CT) L (+ CT) ESRD Risk Reduction: 28% P= Months P L Brenner et al. N Engl J Med. 2001;345:861.

43 Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy Linda F. Fried, M.D., M.P.H., Nicholas Emanuele, M.D., Jane H. Zhang, Ph.D., Mary Brophy, M.D., Todd A. Conner, Pharm.D., William Duckworth, M.D., David J. Leehey, M.D., Peter A. McCullough, M.D., M.P.H., Theresa O'Connor, Ph.D., Paul M. Palevsky, M.D., Robert F. Reilly, M.D., Stephen L. Seliger, M.D., Stuart R. Warren, J.D., Pharm.D., Suzanne Watnick, M.D., Peter Peduzzi, Ph.D., Peter Guarino, M.P.H., Ph.D., for the VA NEPHRON-D Investigators N Engl J Med Volume 369(20): November 14, 2013

44 Study Overview In this study, patients with type 2 diabetes, albuminuria, and mild-to-moderate renal dysfunction received losartan followed by lisinopril or placebo. The study was stopped early because of increased risk of adverse events

45 Kaplan Meier Plot of Cumulative Probabilities of the Primary and Secondary End Points and Death. Fried LF et al. N Engl J Med 2013;369:

46 Fried LF et al. N Engl J Med 2013;369: Safety Outcomes.

47 Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of hyperkalemia and acute kidney injury among patients with diabetic nephropathy and no evidence of benefit.

48 Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients Kenneth Jamerson, M.D., Michael A. Weber, M.D., George L. Bakris, M.D., Björn Dahlöf, M.D., Bertram Pitt, M.D., Victor Shi, M.D., Allen Hester, Ph.D., Jitendra Gupte, M.S., Marjorie Gatlin, M.D., Eric J. Velazquez, M.D., for the ACCOMPLISH Trial Investigators N Engl J Med Volume 359(23): December 4, 2008

49 Study Overview The optimal combination drug therapy for treatment of hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic This double-blind trial, high-risk patients with hypertension were randomly assigned to treatment with benazepril plus either amlodipine or hydrochlorothiazide

50 Effects of Treatment on Systolic and Diastolic Blood Pressure over Time Jamerson K et al. N Engl J Med 2008;359:

51 Kaplan-Meier Curves for Time to First Primary Composite End Point Jamerson K et al. N Engl J Med 2008;359:

52 Hazard Ratios for the Primary Outcome and the Individual Components Jamerson K et al. N Engl J Med 2008;359:

53 Hazard Ratios for Primary, Secondary, and Other Prespecified End Points, and Results of the Subgroup Analysis Jamerson K et al. N Engl J Med 2008;359:

54 Conclusion The benazepril-amlodipine combination was superior to the benazeprilhydrochlorothiazide combination in reducing CV events in patients with hypertension who were at high risk for such events

55 Questions 1. What are the coronary risk factors and risk score? 2. Would you initiate 1 or 2 antihypertensive drugs? 3. What is your target BP? a. < 130/80 mmhg assuming the patient does not have orthostatic hypotension 4. What anti-hypertensive drugs?: a. Start ACEI + amlodipine b. If BP not at goal add chlortalidone C. If BP not at goal add an anti-adrenergic drug (labetalol or carvedilol)