Therapy for Hypertension CAT- Lecture 3

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Therapy for HypertensionCAT- Lecture 3

• By Troy Buchholz MD

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Clinical Questions

• 1. What are the first line medications for pt
  with HTN and CHF?
• 2. What are the best medications to use in
  patients with renal insufficiency?
• 3. What are the best medications to use in the
  pediatric population?

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Treating HTN in patients with CHF
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ACE Inhibitors

• CONSENSUS Trial
• (Cooperative North
  Scandinavian Enalapril Survival Study)
• RCT with follow-up average of 188 days (study
  stopped early- max of 20 months
  follow-up)
• n 253
• NYHA class IV - severe congestive heart failure
• Enalapril 5 mg bid - 20 mg bid vs placebo
• Patients already taking digoxin and diuretics
• Objective mortality rate at 6 months

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Results

• 6 month mortality rate 26 vs 44
• 40 reduction (p 0.002) NNT 6
• 1 yr mortality rate 36 vs 52
• 31 reduction (p 0.001)
• Total mortality at end of study 39 vs 54
• 27 reduction (p 0.003)
• NYHA class improvement 42 vs 22
• A change from class IV to class I or II was seen
  in 16 patients in enalapril
• Enalapril had a significantly greater reduction
  in heart size (p 0.02)
• Trial was discontinued early by the Ethical
  Review Committee due to the results seen above.

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Summary

• 1. Enalapril given to patients with severe
  congestive heart failure is associated with
  considerable reduction in mortality.
• 2. It is important to initiate therapy at low
  doses in class IV CHF patients - 2.5 mg daily
  (due to hypotension)
• Reference Effects of Enalapril on mortality in
  severe congestive heart failure. NEJM 1987
  316 1429-35.

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Vasodilators

• V-HEFT I
• (Veterans Administration Cooperative
  Vasodilator-Heart Failure Trial)
• RCT, 3 treatment arms, follow up 2.3 yrs (max 5.7
  yrs)
• n 642
• criteria for entry evidence of cardiac
  dilation, EF of lt0.45, reduced exercise
  tolerance
• placebo vs prazosin 5-20 mg vs hydralazine 75
  -300mg Isosorbide dinitrate 40-160 mg/day.
• Patients already taking digoxin and diuretics
• Objective compare mortality between the three
  treatment arms.

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Results

• Mortality
• no difference between placebo and prazosin
• 1 yr - 38 reduction in hydralazine/nitrate
• 2 yr - 25 reduction (NNT 11)
• 3 yr - 23 reduction
• for entire follow-up period, reduction in
  mortality in H/N group was borderline
  statistically sign (p .05)
• Ejection Fraction
• Significant rise in H/N group at 8wks and 1 yr
• No sign change in placebo or prazosin groups

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Summary

• 1. Hydralazine/Isosorbide nitrate reduces
  mortality in patients with chronic congestive
  heart failure.
• 2. Hydralazine/Isodorbide nitrate has a favorable
  effect on left ventricular ejection fraction.
• Reference Cohn, Jay N. et.al. Effects of
  vasodilator therapy on mortality in chronic
  congestive heart failure. NEJM 1986 314 1547-52

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Vasodilators vs ACE inhibitors

• V-HEFT II
• (Veterans Administration Cooperative
  Vasodilator-Heart Failure Trial)
• RTC (no placebo) with follow-up of 2.5 yrs (max
  5.7 yrs)
• n 804
• same criteria for entry as V-HEFT I (mild CHF, EF
  of lt0.45)
• enalapril 5-20 mg vs hydralazine 37.5-300mg
  Isosorbide dinitrate 40-160 mg/day.
• Objective compare physiologic endpoints and
  mortality between the two treatment arms.

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Results

• Mortality
• enalapril significantly lower than
  hydralazine/nitrate after 2 yrs - 28 reduction
  (p 0.016) NNT 19
• attributed to a lower number of sudden deaths
• at the end of the study there was no statistical
  difference in mortality rate between the two
  groups
• Ejection fraction
• at 13 weeks and annually to 3 yrs, both had
  significant increases in ejection fraction
• the increase after 13 weeks was significantly
  higher in H/N group (p 0.026)

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Summary

• 1. At 2 yrs, enalapril was found to be superior
  to hydralazine/isosorbide nitrate in reducing
  mortality with CHF
• 2. Both medications increase ejection fraction in
  patients with chronic CHF
• Reference Cohn, Jay N. et.al. A comparison of
  enalapril with hydralazine-isosorbide dinitrate
  in the treatment of chronic congestive heart
  failure.
• NEJM 1991 325 303-10

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Beta blockers

• MERIT-HF trial
• (The Metoprolol CR/XL Randomized Intervention
  Trial in Congestive Heart failure)
• RTC with one year follow-up
• n 3991
• NYHA functional class II to IV, EF of lt 0.40
• Metoprolol CR/XL 25 mg - 200mg/day vs placebo
• Patients already receiving optimal control with
  ACE and diuretic
• Objectives look at mortality, hospitalizations,
  symptoms and quality of life.

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Results

• Total mortality or all-cause hospitalizations
• 19 reduction
• Total mortality or hospitalizations for worsening
  CHF
• 31 reduction (NNT 16)
• Death or heart transplantation
• 32 reduction
• Cardiac death or nonfatal AMI
• 39 reduction

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Results

• Reduced number of any hospitalizations, total
  number of days in hospital due to all causes
  (plt.005)
• Symptoms evaluated by Overall Treatment
  Evaluation (OTE) scores activity limitations,
  symptoms, feelings
• statistically significant improvement in the OTE
  score (P .009)

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Summary

• In patients with mild to severe heart failure due
  to left ventricular systolic dysfunction,
  metoprolol CR/XL improves survival, reduces the
  need for hospitalizations due to worsening heart
  failure, improves symptoms of heart failure and
  increases well being.
• Reference Hjalmarson, Ake, et.al. Effects of
  controlled-release metoprolol on total mortality,
  hospitalizations, and well-being in patients with
  heart failure. JAMA March 8, 2000. 283 (10)
  1295-1302.

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CHF Summary

• ACE inhibitors and B-blockers should be used in
  patients with severe CHF because they reduce
  mortality.
• ACE inhibitors should be chosen over
  hydralazine/nitrate because it has more reduction
  in mortality in patients with mild CHF
• B-blockers improve quality if life in severe CHF.

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Special Populations with HTN

• Renal insufficiency
• Pediatric

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Renal Disease

• JNC VI BP recommendations
• 130/85 in those with lt 1gm of proteinuria per 24
  hrs
• 125/75 in those with gt 1gm of proteinuria per 24
  hrs
• The most important goal in preventing renal
  disease progression is to obtain the above BP
  goals.

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ACE Inhibitors

• There have been multiple randomized trials
  evaluating ACE Inhibitors in patients with renal
  disease.
• They have been shown to reduce the rate of
  progression in nondiabetic chronic renal
  insufficiency in patients with 1-3 g/d of
  proteinuria
• Frequently referenced studies include
• Effect of the angiotensin-converting-enzyme
  inhibitor benazepril on the progression of
  chronic renal insufficiency. NEJM 1996 334
  939-45.

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AIPRI Trial

• Ace Inhibition in Progressive Renal Insufficiency
  Trial.
• ACE inhibitor vs. placebo
• Patients with serum creatinine of lt 2.0 had a 38
  risk reduction in the progression of renal
  disease
• Patients with serum creatinine of gt 2.0 had a 66
  risk reduction in renal disease progression.
• Reference Bakris GL. Short and long-term
  effects of ACE inhibitors on progression of renal
  disease Nephrology 1997 3(suppl 1)S40.

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REIN Trial

• Ramipril Efficacy in Nephropathy Trial.
• Ramipril vs. placebo randomized controlled trial
• Patient who had a serum creatinine of gt2.0 and
  gt3.0 g/d or proteinuria had a 62 risk reduction
  in renal disease progression
• Reference The GISEN Group Randomised
  placebo-controlled trial of effect of ramipril on
  decline of glomerular filtration rate and risk of
  terminal renal failure in proteinuric,
  non-diabetic nephropathy. Lancet
  19973491857-63.)

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AASK Trial

• African American Study of Kidney Disease and
  Hypertension
• Currently the largest comparative drug
  intervention trial focused on renal outcomes.
• 1094 African Americans ages 18-70 with renal
  insufficiency.
• Looked at progression of hypertensive renal
  disease of 2 different BP goals (low and usual)
  and treatment with 1 of 3 medications.

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AASK

• Amlodipine 5-10 mg/d vs. metoprolol 50-200 mg/d
  vs. ramipril 2.5-10 mg/d.
• Clinical endpoints include
• rate of change in GFR rapid decline in renal
  function, end-stage renal disease, death
• In Sept 2000 they withdrew amlodipine arm because
  of a slower decline in mean GRF and reduced rate
  of clinical end points in the ramipril and
  metoprolol groups but not the amlodipine group.
• This study reports the differences seen between
  ramipril and amlodipine metoprolol data still
  unknown.

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AASK preliminary results

• Results
• In patients with proteinuria of gt 300 mg/d,
  ramipril group had a 48 reduction in clinical
  end points vs. the amlodipine group over 3 years
• 36 slower mean decline in GFR
• First 3 months
• 38 reduced risk of clinical end points
• 36 slower mean decline in GFR
• At end of 3 yrs
• No significant differences in mean GFR decline
  from baseline between the two groups

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Summary

• Ramipril, when compared to amlodipine, retards
  renal disease progression in patients with
  hypertensive renal disease and proteinuria.
• Reference Lawrence, Y. Agoda, et.al. Effects
  of Ramipril vs Amlodipine on Renal Outcomes in
  Hypertensive Nephrosclerosis JAMA June 6, 2001.
  285(21) 2719-28.

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Caution with ACE Inhibitors!?

• Elevation in serum creatinine
• One can expect an initial rise of up to 20-30
  from baseline creatinine
• Usually occurs soon after ACE inhibitor is
  started, but may see a rise after months or years
  of therapy
• Should stabilize within 2-3 weeks thus recheck
  serum Cr in 3-4 weeks.
• A useful working definition of acute renal
  failure due to ACE inhibitors may be
• gt0.5 if baseline is lt 2.0
• gt 1.0 if baseline is gt2.0

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Common reason for rise in Cr

• Most common reason is hypovolemia
• seen very commonly in patients with CHF who are
  on diuretics (33 of patients)
• Bilateral renal artery stenosis
• NSAID use
• If ACE inhibitor is stopped, expect a return to
  baseline creatinine within 2-3 days.
• References 1.Bakris, George L. and Matthew R.
  Weir. Angiotensin-Converting-Enzyme
  Inhibitor-Associated Elevations in Serum
  Creatinine. Arch Intern Med Vol 160 Mar 13,
  2000 685-693
• 2. Schoolwerth, Anton C., et.al. Renal
  Considerations in Angiotensin Converting Enzyme
  Inhibitor Therapy. Circulation 2001 1041985-91.

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Summary

• 1. ACE inhibitors should be used 1st line in
  patients with renal disease and hypertension
• Shown to decrease progression of renal disease
  and morbidity
• 2. Expect an initial rise in Cr after starting an
  ACE inhibitor of up to 20-30. Look for other
  reasons - dehydration.
• 3. Still waiting for Metoprolol results.

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Pediatric Population

• Causes
• In late 80s, 84 of patients were found to have
  secondary HTN
• In a study published in 2001, only 51.4 of the
  patients had secondary HTN
• Reason for the shift mainly due to an increase
  in BMI
• Thus treatment of essential HTN becoming more of
  an issue

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Definition

• Guidelines of the National Heart, Lung and Blood
  Institute Task Force.
• Normal BP systolic and diastolic lt 90th
  percentile for age and sex.
• High normal BP average systolic and/or diastolic
  between 90th and 95th percentile
• Significant HTN systolic and/or diastolic gt 95th
  at 3 separate visits
• Severe HTN systolic and/or diastolic gt 99th

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Treatment

• No RCTs supporting use of certain medications in
  pediatric population.
• Mostly retrospective or single center trials with
  low number of patients.
• Reasons
• Lack of industry-sponsored antihypertensive drug
  trials in children
• Lack of manufacturers dosing recommendations
• Lack of age-appropriate drug formulations (only
  few in suspension)

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Currently first-line agents

• Calcium channel blockers
• ACE inhibitors
• Tables 1 and 2
• References
• Flynn, Joseph T. Whats New in Pediatric
  Hypertension. Current Hypertension Reports 2001.
  3 (6) 503-10.
• Temple, Mary E and Milap C. Nahata. Treatment of
  Pediatric Hypertension. Pharmacotherapy 2000
  20(2) 140-50