4/25/15 1 Pharmacologic Interven1on in Hypertension: 2015 Larry Warmoth, M.D. Nephrologist Chief of Staff, Covenant Medical Center Associate Professor of Nephrology, Texas Tech School of Medicine 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 Risk of hypertension (%) Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg Years Life1me Risk of Developing Hypertension Beginning at Age 65 Men Women Vasan RS, et al. JAMA. 2002; 287:1003-1010. Copyright 2002, American Medical Association. www.hypertensiononline.or g
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Pharmacologic Interven1on in Hypertension: 2015
Larry Warmoth, M.D. Nephrologist
Chief of Staff, Covenant Medical Center Associate Professor of Nephrology, Texas Tech School of Medicine
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20Ris
k of
hyp
erte
nsi
on (
%)
Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg
Years
Life1me Risk of Developing Hypertension Beginning at Age 65
Men Women
Vasan RS, et al. JAMA. 2002; 287:1003-1010. Copyright 2002, American Medical Association.
www.hypertensiononline.org
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Frequency Distribu1on of Untreated HTN by Age
Isolated Systolic HTN
Isolated Diastolic HTN
Systolic Diastolic HTN
Hypertension – Why a Nephrologist????
Accurate BP measurement
• Who checks your paIents BP? • You or Staff
• IF Staff – Do they know what to listen for or do they use automated equipment • Seated properly and quietly for 5 minutes • Appropriate size cuff • Inflate 20-‐30 mmHg above loss of radial pulse • Deflate at 2mmHg per second • 1st sound SBP ; Disappearance of Korotkoff sound (phase 5) is DBP • Confirm Elevated blood pressure within 2 weeks • Caffeine, exercise, and smoking should be avoided for at least 30 minutes before BP measurement.
• The auscultatory method should be used. • 24 hour ambulatory BP monitoring
History
• Angina/MI Stroke: ComplicaIons of HTN, Angina may improve with b-‐blockers
• Asthma, COPD: Preclude the use of b-‐blockers • Heart failure: ACE inhibitors indicaIon • DM: ACE preferred • Polyuria and nocturia: Suggest renal impairment
History-‐contd.
• ClaudicaHon: May be aggravated by b-‐blockers, atheromatous RAS may be present
• Gout: May be aggravated by diureIcs • Use of NSAIDs: May cause or aggravate HTN • Family history of HTN: Important risk factor • Family history of premature death: May have been due to HTN
Iden1fiable Causes of HTN
• Sleep apnea • Drug-‐induced or related causes • Chronic kidney disease • Primary aldosteronism • Renovascular disease • Chronic steroid therapy and Cushing’s syndrome • Pheochromocytoma • CoarctaIon of the aorta • Thyroid or parathyroid disease
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Cardiovascular Risk factors
• Hypertension • Cigarece smoking • Obesity (body mass index ≥30 kg/m2) • Physical inacIvity • Dyslipidemia • Diabetes mellitus • Albuminuria or esImated GFR <60 mL/min • Age (older than 55 for men, 65 for women) • Family history of premature cardiovascular disease (men under age 55 or women under age 65)
History-‐contd.
• Family history of DM : PaIent may also be DiabeIc • CigareLe smoker: Aggravate HTN, independently a risk factor for CAD and stroke
• High alcohol: A cause of HTN • High salt intake: Advice low salt intake
Examina1on
• Appropriate measurement of BP in both arms • OpIc fundi • CalculaIon of BMI ( waist circumference also may be useful) • AuscultaIon for caroId, abdominal, and femoral bruits • PalpaIon of the thyroid gland.
Examina1on-‐contd.
• Thorough examinaIon of the heart and lungs • Abdomen for enlarged kidneys, masses, and abnormal aorIc pulsaIon
• Lower extremiIes for edema and pulses • Neurological assessment
Rou1ne Labs
• EKG. • Urinalysis W/ albumin/creaInine and protein/creaInine raIos. • Blood glucose and hematocrit; serum potassium, BUN, creaHnine (eGFR), and calcium.
• HDL cholesterol, LDL cholesterol, and triglycerides.
Development of JNC-8 • Commissioned by the NHLBI in 2008
• Panel members appointed • Developed focused critical questions relevant to practice • Conducted a systematic search of pertinent literature
• Limited to randomized controlled trials (RCTs) published between 1966 and 2009
• Included patients age 18 or older with hypertension • Sample size of 100 patients or more • Results must have included “hard” outcomes • Subsequent search of studies from 2009 to 2013 required samples of
2000 or more patients
James PA et al. JAMA 2014;311:507-‐20.
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Development of JNC-8 • 3 critical questions for adults with hypertension
• Does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes? [When to start therapy?]
• Does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in health outcomes? [How low should I go?]
• Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? [What drug do I use?]
James PA et al. JAMA 2014;311:507-‐20.
Development of JNC-8 • In 2013, the NHLBI decides that it will no longer publish clinical guidelines
• Proposes to work collaboratively with other organizations • The appointed panel members for JNC-8 decided to
publish their findings independently • Published online in JAMA in December 2013 • Received no endorsements from other organizations
James PA et al. JAMA 2014;311:507-‐20.
But Wait…There’s More • A multitude of other hypertension guidelines were also
published in 2013: • AHA/ACC/CDC advisory algorithm • American Society of Hypertension/International Society of
Hypertension (ASH/ISH) • European Society of Hypertension and European Society of
Cardiology (ESH/ESC) • Canadian Hypertension Education Program (CHEP)
JNC-8 Recommendations • In patients >60 years of age, start medications at blood
pressure of >150/90mm Hg and treat to goal of <150/90mm Hg
• In patients >60 years of age, treatment does not need to be adjusted if achieved blood pressure is lower than goal and well-tolerated
James PA et al. JAMA 2014;311:507-‐20.
JNC-8 Recommendations • In patients <60 years of age, start medications at blood
pressure of >140/90mm Hg and treat to goal of <140/90mm Hg
• In all adult patients with diabetes or chronic kidney disease, start medications at blood pressure of >140/90mm Hg and treat to goal of <140/90mm Hg
James PA et al. JAMA 2014;311:507-‐20.
JNC-8 Recommendations • For the non-black population (including diabetes),
initial antihypertensive treatment may include a thiazide, ACEI, ARB, or CCB
• For the black population (including diabetes), initial antihypertensive treatment should include a thiazide or CCB
• For all patients with CKD, initial (or add-on) therapy for hypertension should include an ACEI or ARB
James PA et al. JAMA 2014;311:507-‐20.
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Initial Drug Selection for HTN • What happened to the beta-blockers (BB)?
• Most evidence for BB is from atenolol • Does not meet current FDA criteria for a once-daily drug
• Losartan Intervention for Endpoint reduction (LIFE) study • Compared losartan vs. atenolol in pts. with HTN & LVH • Primary outcome of CV death, MI, or stroke • Overall 13% RRR with losartan vs. atenolol (p=0.021) • Driven mainly by 25% reduction in risk of stroke (p=0.001)
• BB still recommended for many patients with comorbid conditions (CHF, CAD, etc.)
Dahloff B et al. Lancet 2002;359:995-‐1003.
JNC-8 Recommendations • Initiate therapy according to recommendations • If BP is not at goal in one month, increase dose or add a
second agent from recommended classes • If patient is still not at goal, add a third drug from
recommended classes • Do not use an ACEI and ARB together
• Drugs from other classes may be used if additional BP lowering is needed or if contraindications exist
• Refer to HTN specialist whenever necessary
James PA et al. JAMA 2014;311:507-‐20.
Comparisons to Other Guidelines BP Goal JNC-‐7 JNC-‐8 ASH/ISH ESC/ESH CHEP
Age < 60 <140/90 <140/90 <140/90 <140/90 <140/90
Age 60-‐79 <140/90 <150/90 <140/90 <140/90 <140/90
Age 80+ <140/90 <150/90 <150/90 <150/90 <150/90
Diabetes <130/80 <140/90 <140/90 <140/85 <130/80
CKD <130/80 <140/90 <140/90 <130/90 <140/90
Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-‐8.
Comparisons to Other Guidelines JNC-‐7 JNC-‐8 ASH/ISH ESC/ESH CHEP
• DiureIcs: ConsideraIons • Useful for paIents with ISH, African Americans, CHF • Different diureIc classes can be combined for addiIve, or possible synergisIc effects
• Work well in combinaIon with other anIhypertensives • Efficacy drops when renal funcIon becomes seriously impaired
Hypertension
• TherapeuIc OpIons: ACE Inhibitors • ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor
• TherapeuIc OpIons: Angiotensin II Receptor Blockers (ARB’s) • ARB’s block the effects of angiotensin II by compeIng for binding sites at the receptor
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Renin
Angiotensinogen
ACE Angiotensin I
Angiotensin II Non-ACE alternate pathways (eg, chymase)
ARB
AT1 receptors
Vasoconstriction Aldosterone
secretion Renal tubular
reabsorption of sodium and water
Antidiuretic hormone (vasoprressin)
secretion Stimulation of thirst center
Catecholamine secretion
X X
X X
X X ↓ BP
Hypertension Hypertension • ACE inhibitors and ARB’s: Pharmacodynamics
• VasodilaIon • Reduced peripheral resistance • Increased diuresis • Reduced BP • No change in HR • No reducIon in cardiac output
• ARB’s • Same as ACE inhibitors but cough is uncommon
Hypertension
• ACE inhibitors and ARB’s: PotenIal Drug InteracIons
• MedicaIons which promote hyperkalemia • MedicaIons that have acIvity which is sensiIve to changes in serum K+ • MedicaIons that may cause addiIve anIhypertensive effects • NSAIDs
• Diabetes Mellitus (Type 1) with proteinuria • Heart Failure • Post MI with systolic dysfuncIon
• Possible Favorable Effects • Diabetes Mellitus (Type 1 or 2) with proteinuria • Renal Insufficiency
Hypertension
• ACE inhibitors/ARB’s should be carefully considered: • Pre-‐exisIng kidney dysfuncIon (degree of impairment, response to therapy) • Renal artery stenosis (degree of stenosis)
• ACE inhibitors/ARB’s are contraindicated: • Pregnancy • History of angioedema • Hyperkalemia
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Escape of Angiotensin II Despite ACE Inhibi1on
Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972.
Plasma Ang II (pg/mL)
Plasma ACE (nmoL/mL/min)
*
* * * * * * * *
0
10
20
30
Placebo 4 h 24 h 1 2 3 4 5 6
Hospital Months
0 20 40 60 80
100
*P <.001 vs placebo
www.hypertensiononline.org
Hypertension
• TherapeuIc OpIons: Calcium Channel Blockers (CCB’s) • Calcium channel blockers work by blocking calcium channels through which calcium ions enter muscle fibers, controlling hypertension.
• TherapeuIc OpIons: Alpha-‐Beta Blockers • Work by binding to both alpha-‐1 and beta-‐1 and/or beta-‐2 adrenergic receptors consequently prevenIng their acIvaIon by sympatheIc neurotransmicers.
α1-‐sympatholyIcs • beside BP reducIon they reduce benign prostaIc hyperplasia → indicaIon mainly older man with simultaneous BPH • in combinaIon at severe resistant hypertension • posiIvely influence lipidogram • strong 1st dose phenomenon! → postural hypotension, syncopes • prazosin (prototype; Deprazolin), doxazosin (Cardura), terazosin α1-‐lyIc only for the treatment of BPH, without vasodilaIng effects → tamsulosin
α2-‐sympathomimeIcs • central effect – sImulaIon of central α2 receptors through negative feedback inhibit release of norepinephrine on periphery → reflex BP reducIon • α-‐metyldopa (Dopegyt), clonidine • ADR: central depression – sleepiness, bad dreams • clonidine has significant rebound phenomenon • α-‐metyldopa is advantageous during pregnancy – doesn´t influence negaIvely blood circulaIon of fetus
Direct vasodilators hydralazines • specific mechanism of acIon is unknown; probably directly influence contracIle system of vessel wall myocytes • ADR: tachycardia, palpitaIons, fluid retenIon → necessary combinaIons dihydralazine, hydralazine • suitable in pregnancy • hydralazine – genet. polymorphism of biotransformaIon → at slow acetylators can develop as syndrome similar to
lupus erythematodes
Kallium channel openers • opening of K+ channels on the top of myocytes → hyperpolarisaIon → inducIon of relaxaIon
minoxidil • vazodilation in the area of arterioles • retenIon of Na+, hirsuIsm, hypertrichosis → used in the treatment of alopecia
• minoxidil is inexpensive diazoxide • only short-‐term use – at hypertension crisis • induces hyperglycemia – at short-‐term use not macers
Direct renin inhibitors (PRI) • absolutely new group • in many Issues is present own renin system with individual receptors → (pro)renin is bind to cell surfaces; system acts pressorically and proliferaIvely
• it is acIvated when sImulaIon of AT1 receptors decreases → negaIve feedback
• this signal way apparently decreases benefit of ACEI! → inhibiIon of the level of renin → ... becer control
of the whole RAAS → ... possible becer prevenIon of organ damage
Aliskiren • first available peroral PRI • ↓ plasmaIc renin acIvity • indicaIon in 2-‐combinaIon aliskiren + ACEI or aliskirén + ARB → dual inhibiIon of RAAS system • product Rasilez ? -‐ clinical results below expectaIons
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Hypertension in the Elderly • Fastest growing segment of the population • Prevalence of hypertension is very high • Several issues make managing HTN unique:
• Often present with isolated systolic HTN • More likely to present with comorbidities • Many clinical trials in HTN have excluded these patients
(particularly for those 80 years and older) • Elderly are more susceptible to certain adverse effects
(orthostatic hypotension)
HYVET • HYpertension in the Very Elderly Trial
• Randomized, double-blind trial • Included patients aged 80 or older with SBP>160mmHg • Randomized to indapamide +/- perindopril or placebo • Target BP of 150/80mmHg • Primary outcome of fatal or nonfatal stroke
Beckec NS et al. N Engl J Med 2008;358:1887-‐98.
HYVET • Results
• Mean BP at the end of the trial • Indapamide +/- perindopril - 143/78 mm Hg • Placebo – 158/84 mm Hg
• 48.0% of indapamide patients achieved goal BP vs. 19.9% of placebo patients (p<0.001)
• Outcomes with indapamide +/- perindopril • 30% reduction in stroke (p=0.06) • 64% reduction in heart failure (p<0.001) • 21% reduction in all-cause mortality (p=0.02)
Beckec NS et al. N Engl J Med 2008;358:1887-‐98.
Hypertension in the Elderly • HYVET demonstrated that treatment of HTN to goal
BP less than 150/80 mm Hg in patients >80 years old was safe and effective
• But…what about a lower BP goal?
• And…what about the patients age 60-80?
Hypertension in the Elderly • Two “treat-to-target” trials in this age group
• Japanese Trial to Assess Optimal SBP (JATOS) • 4416 patients aged 65-85 (average age of 74) • Randomized to SBP<140 vs. SBP 140-160 • Achieved BP of 136/75 vs. 146/78 • No difference in CV events or renal failure (p=0.99)
• VALISH trial • 3079 patients aged 70-84 (average age of 76) • Randomized to SBP<140 or SBP 140-149 • No significant reductions in stroke, CV events, or renal failure
• Overall event rates were lower than anticipated in both of these studies
JATOS Study Group. Hypertens Res 2008;31:2115-‐27. Ogihara T et al. Hypertension 2010;56:196-‐202.
Hypertension in the Elderly
• Dissension among the ranks!
Wright JT Jr et al. Ann Intern Med 2014;160:499-‐504.
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Hypertension in the Elderly • The opposing arguments:
• The Japanese trials had low event rates and may not represent the risks in other populations
• Data from other studies suggests a goal SBP closer to 140mm Hg may be more appropriate for ages 60-80
• Methodology may have prevented JNC-8 panel from considering the results in their analysis
• The “Speed Limit” effect
Wright JT Jr et al. Ann Intern Med 2014;160:499-‐504.
Pearls
• For resistant HTN – sit down and take a good history • How much water, pop, coffee, milk, juice, tea, ice – anything liquid do you drink daily.
• Food preferences and salt intake • Drugs/Alcohol • Compliance
Pearls cont.
• The only thiazide that will work with an elevated creaInine is metolazone(zaroxolyn)
• If elevated creaInine. Then will need to use a loop diureIc (or with zaroxolyn)
• If potassium is elevated – evaluate current meds and add a diureIc • If potassium is low – ask why • Check for edema – and ask why • Elderly paIents benefit from blood pressure management • Black paIents benefit from ACE/ARB – may need to use larger doses to obtain BP lowering effect
• Severe elevated BP in the upper range of stage II hypertension. • Without progressive end-‐organ dysfuncIon. • Examples: Highly elevated BP without severe headache, shortness of breath or chest pain.
• Usually due to under-‐controlled HTN.
Hypertensive Emergencies
• Severely elevated BP (>180/120mmHg). • With progressive target organ dysfuncIon. • Require emergent lowering of BP. • Examples: Severely elevated BP with: Hypertensive encephalopathy Acute le{ ventricular failure with pulmonary edema Acute MI or unstable angina pectoris DissecIng aorIc aneurysm
Osterberg, L. et al. N Engl J Med 2005;353:487-497
Barriers to Adherence
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Pa1ent Evalua1on Objec1ves
• (1) To assess lifestyle and idenIfy other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment
• (2) To reveal idenIfiable causes of high BP • (3) To assess the presence or absence of target organ damage and CVD
Pearls Cont.
• Metabolic acidosis and hyperkalemia? – use diureIc – loop if creaInine is elevated
• Take blood pressure periodically lying and standing so as not to miss supine hypertension associated with autonomic insufficiency – this is treated differently
• TreaIng SBP and DBP to targets that are <140/90 mmHg • PaIents with diabetes or renal disease, the BP goal is <130/80 mmHg • The primary focus should be on acaining the SBP goal. • To reduce cardiovascular and renal morbidity and mortality
Lifestyle modifica1ons
www.nhlbi.nih.gov
Secondary HTN-‐Clues in Medical History
• Onset: at age < 30 yrs ( Fibromuscular dysplasi) or > 55 (atheloscleroIc renal artery stenosis), sudden onset (thrombus or cholesterol embolism).
• Severity: Grade II, unresponsive to treatment. • Episodic, headache and chest pain/palpitaIon (pheochromocytoma, thyroid dysfuncIon).
• Morbid obesity with history of snoring and dayIme sleepiness (sleep disorders)
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Secondary HTN-‐clues on Exam
• Pallor, edema, other signs of renal disease. • Abdominal bruit especially with a diastolic component (renovascular) • Truncal obesity, purple striae, buffalo hump (hypercorIsolism)
Blood vessels vasodilation of arterial vasculature
Heart: decrease of
Heart rate
AV conduction
Strenght of contraction
Advantages of thiazide diure1cs
• according to more studies thiazide diureIcs are considered the most effecIve
• they increase anIhypertensive effecIvity of combined treatment
• they proved to reach BP normalisaIon • are less expensive than other anIhypertensives
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Reaching BP improvement at specific pa1ents
• Among most paIents is necessary combinaHon of 2 and more anIhypertensives.
• AdminastraIon of other drug should start when monotherapy in required dose doesn´t reduce BP to intended value.
• If the BP is by 20/10 mm Hg higher than intended value, therapy should be started with combinaHon of 2 anHhypertensives.
Other factors influencing selec1on of an1hypertensives
PotenIally prosperous effects: • Thiazide diureHcs slower the process of bone demineralisaIon at osteoporosis
• βB can have posiIve influence at ventricular tachyarrhythmias and fibrilaIons, at migraine, short-‐termly at thyreotoxicosis, at essenIal tremor, perioperaIonal hypertension
• Ca2+B can be applied at Raynaud syndrome and some arrhythmias
Other factors influencing selec1on of an1hypertensives
PotenIally negaIve effects: • thiazide diureHcs at paIents with gout and hyponatremia in anamnesis
• βB at paIents with asthma, allergic diseases of airways and with A-‐V blocks of 2nd and 3rd stage
• ACEI and ARB should not be given if considering pregnancy, are contraindicated in pregnancy, ACEI at angioneuroIc edema
• aldosterone antagonists and K-‐sparing diureIcs can cause hyperkalemia
• TherapeuIc OpIons: Alpha-‐Beta Blockers • Work by binding to both alpha-‐1 and beta-‐1 and/or beta-‐2 adrenergic receptors consequently prevenIng their acIvaIon by sympatheIc neurotransmicers.
• DiureIcs: ConsideraIons • Useful for paIents with ISH, African Americans, CHF • Different diureIc classes can be combined for addiIve, or possible synergisIc effects
• Work well in combinaIon with other anIhypertensives • Efficacy drops when renal funcIon becomes seriously impaired
Hypertension
• TherapeuIc OpIons: ACE Inhibitors • ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor
• TherapeuIc OpIons: Angiotensin II Receptor Blockers (ARB’s) • ARB’s block the effects of angiotensin II by compeIng for binding sites at the receptor
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Renin
Angiotensinogen
ACE Angiotensin I
Angiotensin II Non-ACE alternate pathways (eg, chymase)
ARB
AT1 receptors
Vasoconstriction Aldosterone
secretion Renal tubular
reabsorption of sodium and water
Antidiuretic hormone (vasoprressin)
secretion Stimulation of thirst center
Catecholamine secretion
X X
X X
X X ↓ BP
Hypertension Hypertension • ACE inhibitors and ARB’s: Pharmacodynamics
• VasodilaIon • Reduced peripheral resistance • Increased diuresis • Reduced BP • No change in HR • No reducIon in cardiac output
• ARB’s • Same as ACE inhibitors but cough is uncommon
Hypertension
• ACE inhibitors and ARB’s: PotenIal Drug InteracIons
• MedicaIons which promote hyperkalemia • MedicaIons that have acIvity which is sensiIve to changes in serum K+ • MedicaIons that may cause addiIve anIhypertensive effects • NSAIDs
• Diabetes Mellitus (Type 1) with proteinuria • Heart Failure • Post MI with systolic dysfuncIon
• Possible Favorable Effects • Diabetes Mellitus (Type 1 or 2) with proteinuria • Renal Insufficiency
Hypertension
• ACE inhibitors/ARB’s should be carefully considered: • Pre-‐exisIng kidney dysfuncIon (degree of impairment, response to therapy) • Renal artery stenosis (degree of stenosis)
• ACE inhibitors/ARB’s are contraindicated: • Pregnancy • History of angioedema • Hyperkalemia
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Hypertension in Diabetics • Action to Control CV Risk in Diabetes (ACCORD)
• Randomized, double-blind trial • Included patients with T2DM and high CV risk • Randomized to SBP<120 or SBP<140 • Primary outcome of CV death, MI, or stroke • Results
• Mean SBP of 119 mm Hg vs. 133 mm Hg • No significant difference in primary outcome
(HR=0.88, p=0.2) • Incidence of stroke was lower with intensive
The ACCORD Study Group. N Engl J Med 2010;362:1575-‐85.
Initial Drug Selection for HTN • ALLHAT
• Randomized, double-blind trial • Enrolled 33,357 patients age 55 or older
• Chlorthalidone • Amlodipine • Lisinopril • Doxazosin (this arm stopped early 2° worse outcomes)
• Primary outcome of CHD death or nonfatal MI • No significant difference in primary outcome among the
thiazide, ACEI, or CCB
The ALLHAT CollaboraIve Research Group. JAMA 2002;288:2981-‐97.
Initial Drug Selection for HTN • African-American patients
• High risk for CV events • Less responsive to drugs that act on the renin-angiotensin-
aldosterone system • ACEI, ARB, BB
• Subgroup analysis of black patients in ALLHAT • Less BP reduction with lisinopril than amlodipine • Risk of stroke was significantly higher with lisinopril than with
amlopdipine (RR 1.51, 95% CI 1.22-1.86) • Lisinopril less effective than chlorthalidone in preventing heart
failure, stroke, and combined CHD
The ALLHAT CollaboraIve Research Group. JAMA 2002;288:2981-‐97.