Session 2: Achieving Blood Pressure Goals With Multidrug Therapy—Where Do Renin
Inhibitors Fit In?
Learning Objectives
• Define the scope of hypertensive disease beyond blood pressure to include cardiovascular disease (CVD) risk
factors, disease markers, and target organ damage.
• Achieve and sustain blood pressure targets in hypertensive patients by applying the growing evidence base for
multidrug therapies that include agents that inhibit the renin-angiotensin-aldosterone system (RAAS).
Faculty
Regis R. Vollmer, PhD
Professor, Pharmaceutical Sciences
University of Pittsburgh, School of Pharmacy
Philadelphia, PA
Dr Regis R. Vollmer is a professor of pharmaceutical sciences in the Department of Pharmaceutical
Sciences in the University of Pittsburgh School of Pharmacy. He received a Bachelor of Arts degree
in biological sciences from St Vincent College in Latrobe, PA, and a PhD in cardiovascular
pharmacology from the University of Houston College of Pharmacy. Since joining the faculty at the
University of Pittsburgh in 1977, Dr Vollmer has maintained significant teaching activity in the cardiovascular
physiology and the pathophysiology and pharmacotherapy of cardiovascular disease. He participates in professional and
graduate courses in the University of Pittsburgh Schools of Pharmacy, Dentistry, and Nursing. Dr Vollmer has
published over 50 scientific papers in peer reviewed journals. He has served as an editor for the British Journal of
Pharmacology and is currently an editorial board member of the Journal of Clinical and Experimental Pharmacology.
Currently, he is a co-investigator on a National Institutes of Health–funded study investigating the role of the peptide
oxytocin in salt appetite, food intake, temperature regulation, and susceptibility to stress and anxiety.
Lakesha Butler, PharmD
Clinical Assistant Professor
Ambulatory Care Clinical Pharmacist
Southern Illinois University
Edwardsville, IL
Dr Lakesha Butler is clinical assistant professor in the Department of Pharmacy Practice. She
received her doctorate of pharmacy from Mercer University in Atlanta. Dr Butler completed a
pharmacy practice residency (emphasis on primary care) at the University of Illinois in Chicago.
She practices ambulatory care at the Volunteers in Medicine Clinic, a free clinic in St Charles, MO, specializing in
cardiovascular risk management services. Dr Butler’s research interests include disease state management of diabetes,
hypertension, and dyslipidemia. Her other interests include health disparities, patient medication adherence, and the
development and implementation of pharmacist-managed services.
Faculty Financial Disclosure Statement
The presenting faculty reported the following:
Drs Vollmer and Butler have nothing to disclose.
Education Partner Financial Disclosure Statement
The content collaborators at MW Institute have nothing to disclose.
Drug List
Generic Trade Generic Trade
acebutolol Sectral bumetanide Bumex
aliskiren Tekturna, Tekturna HCT carvedilol various
alprazolam Niravam, Xanax, Xanax XR chlorthalidone various
amlodipine various clonidine various
atenolol Tenormin, Tenoretic clopidogrel Plavix
atorvastatin calcium Caduet, Lipitor cyclobenzaprine Amrix, Flexeril
bendroflumethiazide Corzide, Naturetin digoxin various
diltiazem various
Session 2
diphenhydramine various mometasone Asmanex Twisthaler, Elocon,
doxazosin Cardura, Cardura XL Nasonex
enalapril Lexxel, Teczem, nebivolol Bystolic
Vaseretic, Vasotec nitroglycerin various
eplerenone Inspra olmesartan Azor, Benicar, Benicar HCT
ethacrynic acid Edecrin perindopril Aceon
furosemide Lasix prochlorperazine Compazine, Compro
guanfacine Tenex propranolol various
hydrochlorothiazide various ramipril Altace
leuprolide Eligard, Lupron, Viadur ranitidine Zantac, Tritec
levalbuterol Xopenex, Xopenex HFA tamoxifen Nolvadex, Soltamox
lisinopril Prinivil, Prinzide, valsartan Diovan, Diovan HCT, Exforge
Zestoretic, Zestril verapamil various
loratadine Clarinex, Alavert, Claritin warfarin various
losartan Cozaar, Hyzaar
lovastatin various Investigational
meclizine Antivert bucindolol
metformin various SPP148
minoxidil Loniten, Rogaine, Minodyl, SPP635
Theroxidil SPP676
Suggested Reading List
Atlas S. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care
Pharm. 2007;13(suppl S-b):S9-S20.
Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of
Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289:2073-2082.
Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American
settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens
(Greenwich). 2002;4:393-404.
Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For
Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.
Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of
amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-
Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised
controlled trial. Lancet. 2005;366:895-906.
Dzau V, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: Clinical evidence of improved
patient outcomes: Part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease).
Circulation. 2006;114:2850-2870.
Fisher NDL, Hollenberg NK. Renin inhibition: What are the therapeutic opportunities? J Am Soc Nephrol. 2005;16:592-
599.
Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in
patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study
Group. Lancet. 1998;351:1755-1762.
Kannel WB. Risk Stratification in hypertension: new insights from the Framingham study. Am J Hypertens. 2000;13:3S-
10S.
Oparil S, Yarrows SA, Patel S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with
hypertension: a randomised, double-blind trial. Lancet. 2007;370:221-229.
Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic
heart disease. Circulation. 2007;115:2761-2788.
Stanton A. Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10.
Uresin Y, Taylor AA. Kilo C, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in
combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8:190-198.
Wong ND, Lopez VA, L’Italien G, et al. Inadequate control of hypertension in US adults with cardiovascular disease
comorbidities in 2003-2004. Arch Intern Med. 2007;167:2431-2436.
Session 2
Notes
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Agenda
Learning Objectives
Achieving Blood Pressure Goals 1. Define the scope of hypertensive disease beyond
With Multidrug Therapy – blood pressure to include cardiovascular disease
Where Do Renin Inhibitors Fit In? (CVD) risk factors, disease markers, and target
organ damage.
Regis R. Vollmer, PhD 2. Achieve and sustain blood pressure targets in
Professor of Pharmaceutical Sciences hypertensive patients by applying the growing
School of Pharmacy evidence base for multidrug therapies that include
University of Pittsburgh
Pittsburgh, PA agents that inhibit the renin-angiotensin-aldosterone
Lakesha Butler, PharmD
system (RAAS).
Clinical Assistant Professor
Ambulatory Care Clinical Pharmacist
Southern Illinois University Edwardsville
Edwardsville, IL
Prevalence of Hypertension* in US Adults:
What is Hypertension? NHANES 2005–2006
JNC 7 Definitions
18-39
Blood Pressure (mm Hg) Category *BP ≥ 140/90 mm Hg
40-59
Systolic Diastolic
60 years and over
55 for men, >65 for women
Initial drug choices
Initial drug choices
Diabetes mellitus
OTHERS2
Elevated LDL (or total) cholesterol Without compelling indications
Without compelling indications
With compelling indications
With compelling indications
Left ventricular hypertrophy
Low HDL cholesterol
Renal Disease Stage 11 hypertension
Stage hypertension Stage 2 hypertension Drugs for compelling indications
Drugs for compelling indications
Family history of premature CVD: (SBP 140–159 or DBP 90–99 mm Hg)
Stage 2 hypertension
(SBP ≥160 or DBP ≥100 mm Hg)
(SBP ≥160 or DBP ≥100 mm Hg)
Other antihypertensive drugs
Other antihypertensive drugs
Glucose intolerance (SBP 140–159 or DBP most.
Thiazide-type diuretic for90–99 mm Hg) Two-drug combination for most (diuretic, ACEI, ARB, BB, CCB) as
Thiazide-type diuretic for most. Two-drug combination for most (diuretic,
needed. ACEI, ARB, BB, CCB) as
Women 300 mg did not give an increased BP response, but increased
rate of diarrhea.
Remikiren 0.8 1−2 9.4 ± 4.1 discontinued
No initial dosage adjustment required in elderly patients, or those with
SPP635 NA 25−30 ~24 Phase IIa
mild-to-moderate renal impairment or mild-to-severe hepatic
SPP1148 NA NA NA Phase I insufficiency.
SPP676 NA NA NA Phase I
Caution is advised in patients with severe renal impairment, as clinical
experience is limited.
Poor pharmacokinetic properties have hindered the clinical use Patients should establish a routine pattern for taking aliskiren with
of renin inhibitors developed prior to aliskiren, which received regard to meals. High fat meals decrease absorption substantially.
FDA approval in March 2007
aFor human renin; IC = 50% inhibitory concentration
50
Staessen JA, et al. Lancet. 2006;368:1449-1456.
Medscape. http://www.medscape.com/viewarticle/561678_6. Accessed January 15, 2008. Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR; 2008:2293-4.
Aliskiren: Adverse Reactions
Pharmacokinetic Profile of Aliskiren
6,460 Patients (1740 for ≥ 6 months)
T1/2 approximately 24 hours Treatment discontinued in 2.2% (vs 3.5% for placebo)
supports once-daily dosing
Tmax approximately 1-3 hours post-dose Adverse Effect Aliskiren Placebo
Pharmacokinetics not significantly affected in patients with mild to
severe liver disease GI (diarrhea) 2.3% 1.2%
Renal insufficiency rate and extent of exposure (AUC and Cmax) of Cough 1.1% 0.6%
Aliskiren in subjects with renal impairment did not show a consistent
correlation with the severity of renal impairment Rash 1.0% 0.3%
Starting dose adjustment is therefore unlikely to be required in
patients with hepatic or renal impairment Hyperuricemia 0.4% 0.1%
Bioavailability about 2.5%
Gout 0.2% 0.1%
Kidney stones 0.2% 0%
Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR; 2008:2293-4. Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR; 2008:2293-4.
Aliskiren: Drug Interactions BP Lowering Effects of Aliskiren, Valsartan
or their Combination
Aliskiren is metabolized by CYP 3A4 Baseline SBP (mm Hg) Baseline DBP (mm Hg)
No increase in aliskiren exposure when co-administered 154.2 154.2 154.0 152.7 100.5 100.4 100.3 100.1
0 0
Change in Seated DBP (mm Hg)
Change in Seated SBP (mm Hg)
with:
Lovastatin Digoxin Valsartan
Atenolol Celecoxib Metformin -5 -5
- 4.1
Warfarin HCTZ Amlodipine - 4.6
Furosemide Ramipril
-10 -10
Co-administration of aliskiren reduced AUC and Cmax of
- 9.0*†
furosemide by about 30% and 50%, respectively - 9.7*†
Co-administration of irbesartan reduced Cmax of aliskiren -12.8*† -12.2*
-15 -13.0*† -15
up to 50% after multiple dosing
Co-administration of atorvastatin increased Cmax and AUC -20
-17.2*
-20
of aliskiren by ~50% after multiple dosing Placebo Valsartan Aliskiren Both Placebo Valsartan Aliskiren Both
(n=455) 160-320 150-300 (n=438) (n=455) 160-320 150-300 (n=438)
HCTZ: hydrochlorothiazide (n=453) (n=430) (n=453) (n=430)
Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR; 2008:2293-4. Oparil S, et al. Lancet. 2007;370:221-9. *P 25 kg/m2 300 mg vs
α blocker/
mass index:
inferiority, Placebo or aliskiren in ~6,000 type 2 diabetic hypertensives
ALLAY3 with HTN & LVH Losartan Equivalent
using diabetic complications as the 1° outcome
vasodilator, as L vs A);
(n=465) 100 mg vs needed (L vs A); NS 0.52 for
combination (L vs C) combo
BNP: brain natriuretic peptide; UACR: urinary albumin-to-creatinine ratio
1. McMurray J et al. Paper presented at: European Society of Cardiology Congress; Sept 2, 2007; Vienna, Austria.
2. Parving HH, et al. NEJM. 2008;358:2433-6.
3. Solomon S. Paper presented at: American College of Cardiology; March 31, 2008; Chicago, IL
Possible Combinations of Renin Inhibitors and
Other Antihypertensive Agents
Diuretics1
β-blockers
AT1-receptor
blockers2
CASE STUDY 1
Renin
Inhibitors
α-blockers
Calcium HYPERTENSION IN A
antagonists3
Fixed-dose combination
Fixed-
MIDDLE-AGED MAN
ACE inhibitors4 FDA approved
Emerging evidence
1. US Food and Drug Administration. Drugs@FDA Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
Accessed Feb 29, 2008.
2. Oparil S, et al. Lancet. 2007;370:221-9.
3. Drummond W, et al. J Clin Hypertens 2007;9:742-50.
4. Uresin Y et al. J Renin Angiotensin Aldosterone Syst. 2007;8(4):190-8.
6
Presentation Medical History
43-year-old man
HTN x 1 yr – initial BP 153/95 mm Hg
Hypertension and dyslipidemia
Dyslipidemia x 1 yr
Annual physical examination:
HTN uncontrolled 1 yr after diagnosis, despite Erectile dysfunction (ED) x 6 months
lifestyle counseling by a dietician and
treatment with a diuretic
Blood lipid levels within recommended range
?
Medications Should this man take aspirin 81 mg/d?
Hydrochlorothiazide 25 mg po daily 1. Absolutely, as it prevented about 44% of MIs
in the (male) Physicians’ Health Study
Atorvastatin 10 mg po daily 2. No, there are no clinical trials demonstrating
benefits that included 43-year old men
One multivitamin tablet po daily
3. Unsure if the risk of bleeding outweighs the
potential CVD benefits
4. Yes, if he has a strong family history of CVD
NEJM.1989;321:129-35.
He J, et al. JAMA. 1998;280:1930-5. Antithrombotic Triallists’ Collaboration. BMJ. 2002;324:71-86.
Family History Social History
Father, age 68, HTN, survived an MI at 62 Married with two young children
Mother, age 68, HTN, osteopenia Works as a financial planner for a major
institution
Brother, age 46, no known medical
Coaches son’s little league team on
problems weekends
Sister, age 48, breast cancer, lumpectomy Exercises when schedule allows
and adjuvant therapy
7
Physical Examination
Review of Systems
Supine BP readings:
145/94 mm Hg, P = 78 bpm, regular
Cardiovascular: denies chest discomfort,
142/91 mm Hg, P = 74 bpm, regular
dyspnea, orthopnea, PND and edema
Standing BP readings:
Otherwise non-contributory 156/98 mm Hg, P=84 bpm, regular
Repeated after 2 minutes: 143/90 mm Hg, P=76 bpm,
regular
Patient measurements:
6 ft tall, 212 lbs, waist circumference = 38 in
BMI = 28.8 kg/m2
Physical Examination (cont’d) Laboratory Results
Total cholesterol 150 mg/dL
High density lipoprotein 38 mg/dL
Chest: clear to auscultation 90 mg/dL
Low density lipoprotein
Cardiac: normal S1 and S2 with regular rhythm Triglycerides 112 mg/dL
and rate, no murmurs, gallops or rubs 3.9 mEq/L
Serum potassium
Abdomen: soft, nontender, no organomegaly Serum calcium 10.5 mg/dL ( )
Extremities: no edema, distal pulses 2+ and = Serum creatinine 0.9 mg/dL
eGFR >60 (mL/min/1.73 m ) 2
Albumin/creatinine ratio 28 mg/g
Uric acid 8.2 mg/dL ( )
EKG normal
The patient wishes to avoid antihypertensive ? Incident ED: British Medical Research
medications that are associated with ED. Which Council (MRC)-1 Trial
% of British Men with “Impotence”
class of drugs is most commonly associated 25
22.6*
with ED? *P < .0001
20
1. ACE-inhibitors
15 13.2
2. Beta-blockers
3. Calcium channel blockers 10.1
10
4. Thiazide diuretics
5
~57/566 ~39/282 ~64/282
0
Placebo Propranolol Bendrofluazide
≤ 320 mg/d 5 mg bid
ED: erectile dysfunction Adapted from Lancet. 1981;2:539-43.
8
New ED at 2 Years in TOMHS Presuming the patient is willing to stop the ?
18 17.1* diuretic, which of the following lifestyle
16 modifications has been shown to reduce
*P = .025 vs placebo
% of Men With New ED
14
cardiovascular morbidity in long-term follow-up
of clinical trials?
12
10 1. Calcium supplementation
8.5 8.2
8
Chlorthalidone
6.9 6.8 2. Fish oil supplementation
6
Amlodipine
Acebutolol
4.2 3. Magnesium supplementation
15 mg/d
Enalapril
400 mg/d
5 mg/d
Placebo
4
Doxazosin
5 mg/d
4. Sodium restriction
2 mg/d
2
0
5. Weight loss
Treatment
Grimm RH, et al. Hypertension. 1997;29:8-14. TOMHS:Treatment of Mild Hypertension Study
Long-term Follow-Up in Trials of In addition to advice to reduce his ?
Hypertension Prevention (TOHP) I and II dietary sodium, what other suggestion
TOHP I TOHP II would you make to the licensed health
Cumulative Incidence of CVD
0.04 0.08 0.12 0.16 0.20
Cumulative Incidence of CVD
0.02 0.04 0.06 0.08 0.10
Control Control care provider (HCP)?
Sodium Intervention Sodium Intervention
1. Do not change drugs, but continue to monitor
18 month Intervention 36 - 48 month
Intervention
2. Increase the dose of hydrochlorothiazide
0
0
0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
Follow up (years) Follow up (years) 3. Change hydrochlorothiazide to a different class of
Sodium reduction not only lowers blood pressure antihypertensive drug
but can also reduce long term risk of CV events
4. Add a second drug
After data were combined:
Overall HR = 0.70 (0.53-0.94) P = .018
Cook NR, et al. BMJ. 2007;334:885.
?
What Drug Is Most Likely to be
Added? Follow-Up
1. Angiotensin converting enzyme (ACE) inhibitor Patient calls after 2 weeks of taking the
ACE inhibitor.
2. Angiotensin receptor blocker (ARB) He reports excellent home blood
pressures for the last week, but yesterday
3. Beta blocker
he developed sudden swelling of the lower
4. Calcium channel blocker lip and tongue.
He took some diphenhydramine and
5. Renin inhibitor rested in bed, and only now is he able to
speak to you and ask your advice.
9
?
The ACE inhibitor is most likely to be
replaced by which of the following?
1. A different ACE inhibitor
2. Angiotensin receptor blocker (ARB) CASE STUDY 2
3. Beta blocker
4. Calcium channel blocker
5. Renin inhibitor HYPERTENSION IN A
MIDDLE-AGED WOMAN
Howes LG, et al. Drug Saf. 2002;25:73-6.
Presentation Medical History
Hypertension x 5 years
GERD x 3 years
47-year-old African American woman
Asthma x 14 years
Referred by her cardiologist (and her 9
Allergic rhinitis x 15 years
other physicians) originally in 2004 for
“uncontrollable hypertension for 2 years” Panic/depression x 10 years
Sulfa allergy (with Stevens-Johnson
Syndrome)
Small stroke (without residua) 1 year ago
Other History Evaluation for Secondary HTN
Past surgical history includes TAH/BSO Renal ultrasound: normal
for uterine cancer, and two implanted Renal angiogram: negative
electrical stimulation devices for pain Aldo/PRA ratio: 14
control (s/p MVA in 2002) in 2003 and
24-hour urine: potassium, aldo, VMA,
2004
metanephrines within the reference ranges
She eats a very low-sodium diet, exercises (x 3)
an hour 5 times/week at the local YWCA, CT of abdomen: normal
and has a BMI of 24.5 kg/m2
MRI of abdomen: normal
TAH/BSO: total abdominal hysterectomy / bilateral salpingo-oophorectomy
s/p MVA: status post motor vehicle accident
10
?
Which of the following diuretics is most Abbreviated Medications List
appropriate for this patient? Ethacrynic acid 50 mg bid Tamoxifen 100 mg daily
Atenolol 50 mg daily Leuprolide injection monthly
Lisinopril 40 mg daily Tramadol 100 mg daily
1. Bumetanide Olmesartan 40 mg daily Mometasone 0.25 mg daily
2. Chlorthalidone Amlodipine 10 mg daily Levalbuterol 200 mg prn
Diltiazem 420 mg daily Loratadine 10 mg daily
3. Ethacrynic acid Eplerenone 50 mg bid Mometasone spray bid
Minoxidil 10 mg q 4 hr Diphenhydramine 50 prn
4. Furosemide
Doxazosin 16 mg daily Perchlorperazine 10 mg prn
5. Hydrochlorothiazide Guanfacine 2 mg hs Meclizine 25 mg daily
Atorvastatin 40 mg daily Alprazolam 0.25 mg prn
Aspirin 325 mg daily Hyoscyamine 0.25 mg bid
Clopidogrel 75 mg daily Cyclobenzaprine 10 mg tid
Ranitidine 150 mg hs
Wall GC, et al. Arch Intern Med. 2003;163:116-7.
Which is the most appropriate additional? Selected BPs During Follow-Up
blood pressure medication for this 200
patient?
Blood Pressure (mm Hg)
1. Aliskiren 150 140 mm Hg
2. Carvedilol
100 90 mm Hg
3. Chlorthalidone Aliskiren 150 mg/d
4. Clonidine 50
Aliskiren 300 mg/d
5. Verapamil
0
0 200 400 600 800 1000 1200 1400
Days of Follow-Up
Wall GC, et al. Arch Intern Med. 2003;163:116-7. Data on file. Dr. William Elliott.
Conclusions Conclusions
Hypertension awareness and treatment rates have Many authorities suggest avoiding an ARB after ACE-
improved, but control rates are still not optimal, especially inhibitor-associated angioedema
for high-risk patients
ACEIs and ARBs may provide incomplete RAAS
Hypertension is usually accompanied with one or more blockade due to angiotensin escape and aldosterone
CVD risk factors breakthrough
BP targets for high-risk individuals are < 130/80 mm Hg Renin inhibitors may provide more complete RAAS
or lower blockade by acting at the rate-limiting step
Most high-risk individuals and those with BP ≥ 20/10 mm Oral renin inhibitors are effective in lowering blood
Hg from goal will require 2 or more antihypertensive pressure, especially when combined with other anti-
drugs to reach goal hypertensive drug classes
Long-term lifestyle changes (especially dietary sodium The full benefits of approved hypertension medications
restriction) can reduce BP and significantly lower the risk have yet to be fully defined
for CV events
11