Antihypertensive Combinations: August 2018 Resource #340808

−This Clinical Resource gives subscribers
additional insight related to the Recommendations published in−
August 2018 ~ Resource #340808
Antihypertensive Combinations
Many patients need two or more antihypertensives to reach their blood pressure goal (U.S. subscribers; Canadian subscribers).18 Emphasize lifestyle
changes (e.g., reducing sodium and alcohol intake) and review for conditions (e.g., obstructive sleep apnea) and meds that can raise blood pressure.
Verify adherence and the accuracy of blood pressure readings before adjusting medications. Initiating therapy with two antihypertensives is
recommended in U.S. guidelines for patients who are more than 20 mmHg above their systolic goal or 10 mmHg above their diastolic goal.1,18,19
Using two appropriately chosen antihypertensives can lower blood pressure more and help patients reach blood pressure goals sooner, with fewer side
effects and at lower doses, than using a single drug.1,18 A fixed-dose combination pill may improve adherence compared to using individual
medications.18 Certain combinations are preferred, acceptable, or not preferred based on efficacy, cardiovascular outcomes, side effects, and
adherence.1 This chart provides efficacy, cardiovascular outcomes, side effects, and single pill (i.e., fixed-dose combo) availability information for
various antihypertensive combinations. Not all possible combinations are listed. The chart also provides information to assist in matching patients to
a particular preferred or acceptable combination. When choosing a combination, note that most pivotal studies showing clinical benefit of treating
hypertension included a thiazide.2
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker.
a. Dihydropyridine CCBs = amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine.
b. Non-dihydropyridine CCBs = diltiazem and verapamil.
c. The thiazides chlorthalidone and indapamide provide better 24-hour blood pressure control than hydrochlorothiazide, and were used in
pivotal outcomes studies (e.g., ALLHAT, SHEP, ADVANCE).1,3,10,15,16
d. Charts are available to compare available agents within some of the medications classes used to treat high blood pressure (e.g., ACEIs [U.S.
subscribers], ARBs [U.S. subscribers; Canadian subscribers], beta-blockers [U.S. subscribers; Canadian subscribers], CCBs [U.S. subscribers;
Canadian subscribers], thiazides).
Combinationd Single Pill Combination Availability Comments

Preferred Combinations for Uncomplicated Hypertension
ACEI or ARB plus  Most ACEIs and ARBs available in combination  ACEI/ARB reduces risk of thiazide-induced hypokalemia.1
thiazidec with hydrochlorothiazide.  ACEI/ARB ameliorates diuretic-induced activation of the renin-
 All ACEI/hydrochlorothiazide combos available angiotensin-aldosterone system.1
generically in U.S.  Additive blood pressure reduction.1
 Olmesartan/amlodipine/  Outcomes data for ACEI/thiazide combination (e.g., reduces
hydrochlorothiazide (U.S.)(Tribenzor) stroke, heart failure, mortality, diabetes complications).3,4,7
Continued...
More. . .
Copyright © 2018 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
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(Clinical Resource #340808: Page 2 of 7)

Preferred Combinations, continued
ACEI or ARB plus  Valsartan/amlodipine/hydrochlorothiazide  Consider for chronic renal insufficiency,9,17 diabetes,17 or history
thiazide,c continued (U.S.)(Exforge HCT) of stroke or transient ischemic attack.7,9,17
 Azilsartan/chlorthalidone (Edarbyclor)  An ACE or ARB combined with amlodipine and a thiazide is
associated with additional blood pressure lowering compared to
combinations of two of the individual ingredients.18
ACEI or ARB plus  Benazepril/amlodipine (U.S.)(Lotrel, generics)  ACEI/ARB ameliorates dihydropyridine CCB-induced edema.1
CCBa,b,*  Olmesartan/amlodipine (U.S.)(Azor, generics)  ACEI/ARB counteracts dihydropyridine CCB-induced
 Olmesartan/amlodipine/ sympathetic stimulation (e.g., tachycardia).1
*See comments hydrochlorothiazide (U.S.)(Tribenzor, generics)  Additive blood pressure reduction with both dihydropyridine and
column for  Trandolapril/verapamil (Tarka, generics [U.S.]) non-dihydropyridine CCBs.1,22,23
specifics  Valsartan/amlodipine (U.S.)(Exforge, generics; also  Dihydropyridine outcomes data are primarily with amlodipine.8
distinguishing available with hydrochlorothiazide as Exforge HCT,  Consider for chronic renal insufficiency,17 diabetes,9,17 history of
between generics) stroke or transient ischemic attack,17 and high-risk coronary artery
dihydropyridine  Perindopril/amlodipine (Prestalia [U.S.], Viacoram disease (ACEI plus dihydropyridine [not short-acting
and non- [Canada]) nifedipine]).9
dihydropyridine 
 Telmisartan/amlodipine (Twynsta, generics [U.S.]) Outcomes data for ACEI or ARB/thiazide combination (e.g.,
CCBs. reduces heart failure, myocardial infarction, mortality).8,24
 An ACEI or ARB combined with amlodipine and a thiazide is
associated with additional blood pressure lowering compared to
combinations of two of the individual ingredients.18
Thiazidec, plus  Olmesartan/amlodipine/  Additive blood pressure reduction.21
CCBa,b,* hydrochlorothiazide (U.S.)(Tribenzor, generics])  VALUE study: amlodipine plus hydrochlorothiazide reduced
 Valsartan/amlodipine/ cardiovascular events as well as valsartan plus
*See comments hydrochlorothiazide (U.S.)(Exforge HCT, generics) hydrochlorothiazide [Evidence Level A-1].6
column for  Neither offsets the side effects of the other class (no distinction
specifics between dihydropyridine and non-dihydropyridines).1
distinguishing  An ACE or ARB combined with amlodipine and a thiazide is
between associated with additional blood pressure lowering compared to
dihydropyridine combinations of two of individual ingredients.18
and non-  Dihydropyridine CCBs plus a thiazide may be a preferred
dihydropyridine combination in the black patients, the elderly, or patients with
CCBs. isolated systolic hypertension due to the stroke protection with
both classes compared to other antihypertensives.19-21
More. . .

Acceptable Combinations for Uncomplicated Hypertension: Consider based on patient factors (e.g., comorbidities, antihypertensive response
history, contraindications/potential safety issues with preferred agents, cost).
Thiazidec plus  Aliskiren/hydrochlorothiazide  Aliskiren reduces risk of thiazide-induced hypokalemia.1
aliskiren (Tekturna HCT [U.S.], Rasilez HCT [Canada])  Ameliorates thiazide-induced activation of the renin-angiotensin-
aldosterone system.1
 Additive blood pressure reduction.1
 Reserve for patients unable to tolerate an ACEI, ARB, or other
preferred antihypertensive. See our chart, ACEI, ARB, and
Aliskiren Comparison.
Thiazidec plus beta-  Atenolol/chlorthalidone (Tenoretic, generics)  Beta-blockers ameliorate thiazide-induced activation of renin-
blocker  Bisoprolol/hydrochlorothiazide (U.S.) angiotensin-aldosterone system.1
(Ziac, generics)  Additive blood pressure reduction.1
 Metoprolol tartrate/hydrochlorothiazide  Thiazides improve beta-blocker efficacy in African Americans.1
(U.S.)(Lopressor HCT, generics)  Side effects (fatigue, sexual dysfunction, glucose intolerance)
 Metoprolol succinate/hydrochlorothiazide may be problematic.1
(U.S.)(Dutoprol, generics)  Beta-blockers seem less effective than other antihypertensive
 Nadolol/bendroflumethiazide (U.S.)(Corzide, classes for improving outcomes in hypertension (most data are
generics) from studies using atenolol).5
 Propranolol/hydrochlorothiazide (U.S.)  Reserve for patients with hypertension plus another condition that
 Pindolol/hydrochlorothiazide (Canada)(Viskazide) would benefit from a beta-blocker (e.g., heart failure, post-
myocardial infarction, angina, migraine prophylaxis).5,9,17 See our
charts, Target Doses of Meds for Systolic Heart Failure and
Target Doses of Post-MI Medications, for evidence-based
choices.
Thiazidec plus  Hydrochlorothiazide/amiloride (Novamilor  Spironolactone, amiloride, or triamterene offsets thiazide-induced

potassium-sparing [Canada], generics) hypokalemia.1
diuretic  Hydrochlorothiazide/triamterene (Maxzide [U.S.],  Blood pressure reduction variable.1
Dyazide [U.S.], generics)  Risk of hyperkalemia in patients with creatinine clearance of
 Hydrochlorothiazide/spironolactone (Aldactazide, 50 mL/min or less.1
generics)  No outcomes data.
More. . .

Acceptable combinations, continued
Beta-blocker plus  None  Additive blood pressure reduction.1
dihydropyridine  No outcomes data.1
CCBa  Reserve for patients with hypertension plus another condition that
would benefit from a beta-blocker (e.g., heart failure, post-MI,
angina, migraine prophylaxis).5,9,17 See our charts, Target Doses
of Meds for Systolic Heart Failure and Target Doses of Post-MI
Medications, for evidence-based choices.
Aliskiren plus  None  No outcomes data.

CCBa,b  Reserve aliskiren for patients who can’t take an ACEI or ARB.
ACEI or ARB plus  Nebivolol/valsartan (U.S.)(Byvalson)  Combination provides little additional blood pressure lowering.1
beta-blocker However, combination is appropriate for patients who also have
systolic heart failure or post-MI.1 See our charts, Target Doses of
Meds for Systolic Heart Failure and Target Doses of Post-MI
Medications, for evidence-based choices.
Dihydropyridine  None  Additive blood pressure reduction.19

CCB plus non-  No outcomes data.
dihydropyridine  Non-dihydropyridine CCBs should be avoided in patients with
CCBa,b reduced ejection fraction heart failure.19
Not Preferred Combinations for Uncomplicated Hypertension

ACEI plus ARB  None  Combination provides little additional blood pressure lowering
with more adverse effects (e.g., hyperkalemia, syncope) than
monotherapy and no cardiovascular outcomes benefit.1,14,19
 Not recommended per guidelines.9,19
 May have role in systolic heart failure.1,14
More. . .

Not Preferred Combinations, continued
Aliskiren plus ARB  None  Combination provides little additional blood pressure lowering
or ACEI with more adverse effects than monotherapy, and no
cardiovascular outcomes data in hypertesion.1,14
 Aliskiren added to ACEI or ARB in patients with diabetes plus
renal impairment and/or cardiovascular disease increased risk of
hyperkalemia and hypotension.11
o Avoid combo in patients with diabetes or moderate to severe
renal impairment.12,13
 Consider a preferred ACEI or ARB combo first.
Non-  None  Risk of heart block and bradycardia.1

dihydropyridine
CCBb plus beta-
blocker
Methyldopa plus  None  Risk of heart block and bradycardia.1

beta-blocker  Abrupt discontinuation can cause hypertensive crisis.1
Clonidine plus  None  Risk of heart block and bradycardia.1

beta-blocker  Abrupt discontinuation can cause hypertensive crisis.1
Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical
judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and internet links in this article were current as of the date of publication.
More. . .
Levels of Evidence 4. Beckett NS, Peters R, Fletcher AE, et al. Treatment

In accordance with our goal of providing Evidence- of hypertension in patients 80 years of age or older.
N Engl J Med 2008;358:1887-98.
Based information, we are citing the LEVEL OF 5. Clinical Resource, Atenolol for Hypertension.
EVIDENCE for the clinical recommendations we Pharmacist's Letter/Prescriber's Letter. January
publish. 2013.
Level Definition Study Quality 6. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in
hypertensive patients at high cardiovascular risk
A Good-quality 1. High-quality RCT treated with regimens based on valsartan or
patient-oriented 2. SR/Meta-analysis of amlodipine: the VALUE randomised trial. Lancet
evidence.* RCTs with consistent 2004;363:2022–31.
findings 7. PROGRESS Collaborative Group. Randomised trial
3. All-or-none study of a perindopril-based blood-pressure-lowering
B Inconsistent or 1. Lower-quality RCT regimen among 6,105 individuals with previous
limited-quality stroke or transient ischaemic attack. Lancet
2. SR/Meta-analysis
patient-oriented 2001;358:1033-41.
with low-quality
evidence.* 8. Jamerson K, Weber MA, Bakris GL, et al. Benazepril
clinical trials or of
plus amlodipine or hydrochlorothiazide for
studies with
hypertension in high-risk patients. N Engl J Med
inconsistent findings
2008;359:2417-28.
3. Cohort study
9. Nerenberg KA, Zarnke KB, Leung AA, et al.
4. Case control study
Hypertension Canada’s 2018 guidelines for
C Consensus; usual practice; expert opinion; diagnosis, risk assessment, prevention, and
disease-oriented evidence (e.g., physiologic or treatment of hypertension in adults and children.
surrogate endpoints); case series for studies of Can J Cardiol 2018;34:506-25.
diagnosis, treatment, prevention, or screening. 10. Chobanian AV. Does it matter how hypertension is
*Outcomes that matter to patients (e.g., morbidity, mortality,
controlled? N Engl J Med 2008;359:2485-8.
symptom improvement, quality of life).
RCT = randomized controlled trial; SR = systematic review 11. Parving HH, Brenner BM, McMurray JJ, et al.
[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Cardiorenal end points in a trial of aliskiren for type 2
Recommendation Taxonomy (SORT): a patient-centered approach to diabetes. N Engl J Med 2012;367:2204-13.
grading evidence in the medical literature. Am Fam Physician 12. Product information for Tekturna. Noden Pharma
2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.] USA. Boston, MA 02116. November 2017.
13. Product monograph for Rasilez. Noden Pharma
DAC. Dublin 2, Ireland. January 2018.
14. Clinical Resource, ACEI, ARB, and Aliskiren
Project Leader in preparation of this clinical Comparison. Pharmacist’s Letter/Prescriber’s Letter.
resource (340808): Beth Bryant, Pharm.D., BCPS, March 2016.
Assistant Editor 15. Radevski IV, Valtchanova ZP, Candy GP, et al.
Comparison of indapamide and low-dose
hydrochlorothiazide monotherapy in black patients
with mild to moderate hypertension. S Afr Med J
References 2002;92:532-6.
1. Gradman AH, Basile JN, Carter BL, et al. 16. Prevention of stroke by antihypertensive drug
Combination therapy in hypertension. J Am Soc treatment in older persons with isolated systolic
Hypertens 2010;4:42-50. hypertension. Final results of the Systolic
2. James PA, Oparil S, Carter BL, et al. 2014 Hypertension in the Elderly Program (SHEP). SHEP
evidence-based guideline for the management of Cooperative Research Group. JAMA
high blood pressure in adults: report from the panel 1991;265:3255-64.
members appointed to the Eighth Joint National 17. Weber MA, Schiffrin EL, White WB, et al. Clinical
Committee (JNC 8). JAMA 2014;311:507-20. practice guidelines for the management of
3. Patel A, ADVANCE Collaborative Group, MacMahon hypertension in the community: a statement by the
S, et al. Effects of a fixed combination of perindopril American Society of Hypertension and the
and indapamide on macrovascular and International Society of Hypertension. J Clin
microvascular outcomes in patients with type 2 Hypertens (Greenwich) 2014;16:14-26.
diabetes mellitus (the ADVANCE trial): a 18. Lopatowska P, Mlodawska E, Tomaszuk-Kazberuk
randomised controlled trial. Lancet 2007;370:829- A, et al. Adhering to principles of clinical
40. pharmacology – the correct fixed combinations of
antihypertensive drugs. Expert Rev Clin Pharmacol
2018:11:165-70.
More. . .
pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~
nursesletter.therapeuticresearch.com
19. Whelton PK, Carey RM, Aronow WS, et al. 2017 21. Rimoldi SF, Messerli FH, Chavez P, et al. Efficacy
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC and safety of calcium channel blocker/diuretics
/NMA/PCNA Guideline for the prevention, detection, combination therapy in hypertensive patients: a
evaluation, and management of high blood pressure meta analysis. J Clin Hypertens (Greenwich)
in adults: a report of the American College of 2015;17:193-9.
Cardiology/American Heart Association Task Force 22. Product information for Lotrel. Novartis
on Clinical Practice Guidelines. J Am Coll Cardiol Pharmaceuticals. East Hanover, NJ 07936. July
2018;71:e127-248. 2017.
20. Piepoli MF, Hoes AW, Agewall S, et al. 2016 23. Product information for Tarka. AbbVie. North
European guidelines on cardiovascular disease Chicago, IL 60064. June 2018.
prevention in clinical practice: the Sixth Joint Task 24. Kim-Mitsuyama S, Ogawa H, Matsui K, et al. An
Force of the European Society of Cardiology and angiotensin II receptor blocker-calcium channel
Other Societies on Cardiovascular Disease blocker combination prevents cardiovascular events
Prevention in Clinical Practice (constituted by in elderly high-risk hypertensive patients with chronic
representatives of 10 societies and by invited kidney disease better than high-dose angiotensin II
experts) developed with the special contribution of receptor blockade alone. Kidney Int 2013;83:167-76.
the European Association for Cardiovascular
Prevention & Rehabilitation (EACPR). Eur Heart J
2016;37:2315-81.
Cite this document as follows: Clinical Resource, Antihypertensive Combinations. Pharmacist’s Letter/Prescriber’s
Letter. August 2018.
Evidence and Recommendations You Can Trust…
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Copyright  2018 by Therapeutic Research Center
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PL Detail-Document #280502
−This Detail-Document accompanies the related article published in−
PHARMACIST’S LETTER / PRESCRIBER’S LETTER
May 2012
Characteristics of the Various Statins

―Based on U.S. product labeling and relevant studies. Canadian product information given if differs significantly (e.g., more conservative) from U.S. (Full update
November 2013)―
View our helpful PL Chart, Non-Statin Lipid-Lowering Agents

Druga Potency (average Renal Liver Function Selected Drug Interactions Cost/month
decrease in Considerations Monitoringc (U.S./
LDL)1,2,8 Canada)b
Atorvastatin 10 mg: 35-39% No dose Check liver function Metabolized by CYP3A4, but less than 10 mg:
(Lipitor, generics) 20 mg: 43% adjustment tests at baseline and lovastatin and simvastatin. Some drugs $7.08
40 mg: 50% necessary for when clinically that significantly inhibit its metabolism (generic)/
80 mg: 55-60% reduced renal indicated.4 through CYP3A4 inhibition include $10.17
function. amiodarone, erythromycin, (generic)
(Use 10 mg clarithromycin, telithromycin,
daily in patients itraconazole & other azoles, nefazodone,
with renal protease inhibitors, cyclosporine, and
disease per grapefruit juice; atorvastatin dose
Canadian reduction or discontinuation may be
labelling.) recommended. Consider cautious dosing
with niacin or fibrates (avoid
gemfibrozil). Rifampin may increase or
decrease levels, depending on timing.
Fluvastatin 20 mg: 22% In severe renal Check liver function Metabolized primarily by CYP2C9. Few 80 mg XL:
(Lescol, generics; 40 mg: 25% impairment, use tests at baseline (and significant interactions with 2C9 $162.24/
Lescol XL) 80 mg: 35% daily doses over 8 weeks after initiation inhibitors.3 May be less likely to be $49.39
(as XL product) 40 mg with or dosage increase, per involved in drug interactions. Use with
caution. Canadian labelling) and phenytoin or glyburide can increase
(Canadian when clinically levels of both drugs. Consider dose
labelling indicated.4 reduction with niacin. Caution with
recommends not fibrates (avoid gemfibrozil). Max dose
using if CrCl 20 mg twice daily with cyclosporine or
<30 mL/min.) fluconazole. Rifampin decreases levels.
More. . .
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com
(PL Detail-Document #280502: Page 2 of 9)
LDL)1,2,8 Canada)b
Lovastatin 10 mg: 21% If CrCl Check liver function Metabolized by CYP3A4. 40 mg:
(Mevacor, generics) 20 mg: 24-27% <30 mL/min, tests at baseline (and Contraindicated with strong CYP3A4 $<5
40 mg: 30-31% use daily doses periodically, per inhibitors including erythromycin, (generic)/
80 mg: 40-42% over Canadian labelling clarithromycin, telithromycin, $29.11
(as 40 mg BID) 20 mg with [more frequent with itraconazole, ketoconazole, (generic)
caution. 40 mg or more]) and posaconazole, voriconazole, protease
when clinically inhibitors, and nefazodone. Avoid
indicated.4 grapefruit and cyclosporine
(cyclosporine contraindicated [Canada]).
Do not exceed 40 mg daily with
amiodarone. Do not exceed 20 mg daily
with diltiazem, verapamil, danazol,
dronedarone, or niacin >1000 mg/day
(Canada), or 40 mg daily with extended-
release niacin (Niaspan). Consider dose
reduction with ranolazine. Caution with
fibrates (avoid gemfibrozil; do not
exceed 20 mg daily with fibrates
[Canada]).
Pitavastatin 1 mg: 29% For glomerular Check liver function Not significantly metabolized by 2 mg:
(Livalo) (U.S. only) 2 mg: 36-39% filtration rate tests at baseline and cytochrome P450 and may be less likely $150
4 mg: 41-45% (GFR) 15-59 when clinically to be involved in drug interactions.
mL/min/1.73m2, indicated.4 Contraindicated with cyclosporine.
including Limit dose to 1 mg daily with
hemodialysis, erythromycin or 2 mg daily with
initial daily dose rifampin. Consider dosage reduction
is 1 mg, max with niacin. Caution with fibrates (avoid
daily dose is gemfibrozil).
2 mg.
More. . .
LDL)1,2,8 Canada)b
Pravastatin 10 mg: 22% In significant Check liver function Not significantly metabolized by 40 mg:
(Pravachol, generics) 20 mg: 29% renal tests at baseline (and cytochrome P450 and may be less likely $18.82
40 mg: 34% impairment, 12 weeks after to be involved in drug interactions. Do (generic)/
80 mg: 37% start with 10 mg initiation or dosage not exceed 20 mg once daily with $18.65
daily. increase, per Canadian cyclosporine. Do not exceed 40 mg once (generic)
(Canadian labelling), and when daily with clarithromycin. Caution with
labelling advises clinically indicated.4 fibrates (avoid gemfibrozil). Consider
caution with dose reduction with niacin
daily doses >1000 mg/day.
of 40 mg or
more in renal
impairment.)
Rosuvastatin 5 mg: 45% If CrCl <30 Check liver function Not significantly metabolized by 5 mg:
(Crestor, generics 10 mg: 46-49% mL/min/1.73 m2 tests at baseline (and cytochrome P450 and may be less likely $171.33/
[Canada]) 20 mg: 50-55% (but not on 12 weeks after to be involved in drug interactions. $10.45
40 mg: 55-63% hemodialysis), initiation, and before Substrate of transporter proteins (generic)
starting dose is and 12 weeks after OATP1B1 and BCRP. Drugs that may
5 mg daily, titration to 40 mg, per increase rosuvastatin levels include
maximum Canadian labelling), dronedarone and itraconazole. Caution
10 mg daily. and when clinically with niacin. Limit to 10 mg with
Rosuvastatin indicated.4 lopinavir/ritonavir or
levels in atazanavir/ritonavir. Use caution with
hemodialysis other protease inhibitor/ritonavir
patients are combos. Protease inhibitor use
about 50% discouraged in Canadian labelling.
higher than Canada: cyclosporine contraindicated.
levels in normal Rosuvastatin 40 mg contraindicated with
renal function. fibrate or niacin.
U.S.: max rosuvastatin dose 5 mg with
cyclosporine, and 10 mg with
gemfibrozil (avoid gemfibrozil
preferred); caution with fenofibrate.
More. . .
LDL)1,2,8 Canada)b
Simvastatin 5 mg: 26% In severe renal Check liver function Metabolized by CYP3A4. 20 mg:
(Zocor, generics) 10 mg: 29% impairment, tests at baseline and Contraindicated with strong CYP3A4 $<4
20 mg: 38% starting dose is when clinically inhibitors including erythromycin, (generic)/
40 mg: 30-41% 5 mg daily with indicated.4 clarithromycin, telithromycin, $20.26
80 mg: 36-47% close (Per Canadian itraconazole, ketoconazole, (generic)
monitoring. labelling, for patients to posaconazole, voriconazole, protease
(Per Canadian be titrated to 80 mg, inhibitors, and nefazodone.
labelling, check prior to dosage Cyclosporine and danazol
caution with increase, three months contraindicated. Avoid grapefruit. Do
doses >10 mg later, then periodically not exceed 20 mg daily with amiodarone,
daily with [e.g., semiannually] for amlodipine, ranolazine, or lomitapide.
severe renal the first year.) Do not exceed 10 mg daily with
impairment diltiazem, verapamil, or dronedarone.
[CrCl Do not exceed 40 mg daily with
<30 mL/min].) extended-release niacin (Niaspan), in
Chinese patients taking >1 g/day niacin,
or with lomitapide in patients who have
previously tolerated simvastatin 80 mg.
Contraindicated with gemfibrozil.
Caution with fibrates (do not exceed
10 mg with fenofibrate [Canada]).
a. The following product labeling was used for the above chart: Lipitor (October 2012), Lescol/Lescol XL (October 2012), Mevacor (October 2012),
Livalo (October 2013), Pravachol (October 2012), Crestor (August 2013), Zocor (October 2013), Niaspan (March 2013), Lipitor Canada (May
2013), Lescol/Lescol XL Canada (September 2013), Mevacor Canada (April 2013), Pravachol Canada (January 2013), Crestor Canada (May 2013),
Zocor Canada (March 2013).
b. U.S. cost is wholesale average cost (WAC). Canadian cost is wholesale cost. Cost is for generic if available.
c. Tell statin users to stop the statin and report symptoms of liver injury (e.g., jaundice, abdominal pain, etc) right away. Stop the statin in the event
of evidence of liver injury (e.g., elevated direct bilirubin level, hepatomegaly, jaundice, increased prothrombin time). 5,6 If the statin cannot be
excluded as a cause of liver injury, do not restart a statin. 5 But if elevated transaminase levels are the only problem, experts recommend continuing
the statin.5 There’s no proof that dose reduction is necessary.5 If transaminases exceed three times the upper limit of normal, repeat the test. 6 In
asymptomatic patients with transaminases less than five times normal and no evidence of liver injury, the repeat test can be deferred for six months.
More. . .
In the meantime, stop alcohol and hepatotoxic medications, encourage weight loss, and control diabetes. 7 If still elevated, rule out other causes and
consider decreasing the dose or stopping the statin.6
Abbreviations: ACS = acute coronary syndrome; CHD = coronary heart disease; HDL = high-density lipoprotein cholesterol; LDL = low-density
lipoprotein cholesterol; MACE = major adverse cardiac event (cardiac death, non-fatal MI, or revascularization); MI = myocardial infarction; OATP
= organic anion transporting polypeptide; PCI = percutaneous coronary intervention; TIA = transient ischemic attack. Evidence is Level A for all
studies except CARDS, FLORIDA, TREADMILL [Level A/B] and GREACE and L-CAD [Level B].
Clinical Benefit of Statins (Study acronym in parentheses; FDA-labeled indications are underlined. Full update April 2012.)
Atorvastatin (Lipitor)
▪ Primary prevention of CHD: Reduces non-fatal MI and fatal CHD, and stroke in patients with hypertension and total cholesterol <250 mg/dL
(ASCOT).
▪ Primary prevention of CHD in diabetes: Reduces stroke and MI in patients with type 2 diabetes, an additional CHD risk factor, and LDL
<160 mg/dL (CARDS).
▪ Secondary prevention of CHD: 80 mg/day reduced risk of major cardiovascular events in patients with CHD and LDL<130 mg/dL vs 10 mg. No
overall mortality difference (TNT).
Secondary prevention of CHD: 80 mg/day reduced risk of non-fatal cardiovascular events vs simvastatin 40-80 mg/day in patients with CHD and
previous MI (mean LDL 121.5 mg/dL) (IDEAL).
▪ Secondary prevention of CHD:* Reduced risk of coronary morbidity and mortality, and stroke in open-label comparison with usual care of patients
with LDL >100 mg/dL (GREACE). (*Note: GREACE not used to support this indication.)
▪ 80 mg/day begun within 1 to 4 days after ACS reduced recurrent ischemic events and stroke over 4 months (MIRACL).
▪ In ACS, intense lipid lowering (median LDL 62 mg/dL) lowers risk of death/major cardio events more than moderate lipid lowering (median LDL
95 mg/dL) (PROVE-IT).
▪ Regresses/slows progression of atherosclerosis (ASAP, ARBITER, REVERSAL).
▪ Unclear benefit in peripheral arterial disease (TREADMILL).
More. . .
Fluvastatin (Lescol)
▪ Slows progression of atherosclerosis in patients with CHD and mild to moderate hypercholesterolemia (LCAS).
▪ Secondary prevention of CHD: Reduces need for revascularization. Dose of 40 mg twice daily reduced risk of MACE when begun within days
after PCI in patients with average cholesterol levels (LIPS).
▪ Did not reduce MACE in renal transplant recipients, but secondary endpoints of cardiac death and MI were reduced (ALERT).
▪ No benefit for early treatment of ACS with 80 mg/day (FLORIDA).
Lovastatin (Mevacor)
▪ Primary prevention of CHD: Reduces first acute coronary event, MI, unstable angina, and revascularization in patients with average LDL
(AFCAPS/ TexCAPS).
▪ Slows progression of coronary atherosclerosis in CHD (CCAIT, FATS, MARS). Improvement also in carotid arteries (ACAPS).
Pitavastatin (Livalo)
▪ Pitavastatin 4 mg and atorvastatin 20 mg similarly reduce nonculprit coronary plaque volume post-ACS (JAPAN-ACS).
Pravastatin (Pravachol)
▪ Primary prevention of CHD: Reduces cardiovascular death, MI, and revascularization in patients with high LDL and multiple risk factors
(WOSCOPS).
▪ Secondary prevention of CHD: Reduces recurrent MI, coronary death, revascularization, and stroke/TIA across range of cholesterol levels (CARE,
LIPID).
▪ Slows progression of coronary atherosclerosis in CHD; improvement also in carotid arteries (REGRESS, PLAC I, PLAC II, KAPS).
▪ Failed to show benefit in hypertensive patients (ALLHAT-LLT), but result probably due to high non-study statin use in usual care group.
▪ Preliminary study found lower risk of MACE with early therapy of ACS (L-CAD).
▪ Reduced composite of coronary death, non-fatal MI, and stroke in high-risk patients >70 years old, but no benefit for stroke alone; result attributed
to short study duration (PROSPER).
More. . .
Rosuvastatin (Crestor)
▪ Regression of atherosclerosis with intensive statin therapy in patients with angiographic coronary disease.
▪ 40 mg/day reduced LDL (mean 60.8 mg/dL), raised HDL (mean 49.0 mg/dL), and reduced percent mean atheroma volume by 0.98% (ASTEROID).
▪ Slows progression of atherosclerosis (METEOR).
▪ Primary prevention of CAD: Reduces MI, stroke, and cardiovascular death in patients with LDL <130 mg/dL and hs-CRP >2 mg/L (JUPITER).
Simvastatin (Zocor)
▪ Primary and secondary prevention of CHD: Reduces risk of total mortality, non-fatal MI, stroke, and revascularization in patients at high risk of
coronary eventsc, but with normal cholesterol (including LDL <100 mg/dL, women, diabetes, and peripheral arterial disease) (HPS).
▪ Secondary prevention of CHD: Reduces recurrent MI, coronary and total mortality, revascularization, and stroke in patients with high LDL (4S).
▪ Slows progression of atherosclerosis in patients with CHD and normal to high cholesterol (MAAS, SCAT).
▪ Combined with niacin reduces major coronary events in patients with CHD and HDL <35 mg/dL (HATS).
▪ Reduces vascular events (HPS) and development/progression of intermittent claudication (4S) in peripheral arterial disease.
c. In patients with CHD or CHD risk-equivalent (diabetes, peripheral arterial disease, history of stroke or other cerebrovascular disease).
Statin Clinical Trials

4S - Scandinavian Simvastatin Survival Study: Lancet 1994;344:1383-9. Am J Cardiol 1998;81:333-5.
ACAPS - Asymptomatic Carotid Artery Progression Study: Circulation 1994;90:1679-87.
AFCAPS/TEXCAPS - Air Force/Texas Coronary Atherosclerosis Prevention Study: JAMA 1998;279:1615-22.
ALERT - Assessment of Lescol in Renal Transplantation Study: Lancet 2003;361:2024-31.
ALLHAT-LLT - Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JAMA 2002;288:2998-3007.
ARBITER - Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: Circulation 2002;106:2055-60.
ASAP - Atorvastatin versus Simvastatin on Atherosclerosis Prevention: Lancet 2001;357:577-81.
ASCOT - Anglo-Scandinavian Cardiac Outcomes Trial: Lancet 2003;361:1149-58.
ASTEROID - A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden: JAMA
2006;295:1556-65.
CARDS - Collaborative Atorvastatin Diabetes Study. Lancet 2004;364:685-96.
CARE - Cholesterol and Recurrent Events Trial: N Engl J Med 1996;335:1001-9.
CCAIT - Canadian Coronary Atherosclerosis Intervention Trial: Circulation 1994;89:959-68. Circulation 1995;92:2404-10.
More. . .
FATS - Familial Atherosclerosis Treatment Study: N Engl J Med 1990;323:1289-98.

FLORIDA - Fluvastatin on Risk Diminishing after Acute Myocardial Infarction: [Abstract] Circulation 2000;102:2672d.
GREACE - GREek Atorvastatin and Coronary-heart-disease Evaluation study: Curr Med Res Opin 2002;18:220-8.
HATS - HDL Atherosclerosis Treatment Study: N Engl J Med 2001;345:1583-92.
HPS - Heart Protection Study: Lancet 2002;360:7-22. Lancet 2003;361:2005-16.
IDEAL - Incremental Decrease in End points through Aggressive Lipid lowering. JAMA 2005;294:2437-45.
JAPAN-ACS - Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter
randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of
pitavastatin and atorvastatin in acute coronary syndrome] study. J Am Coll Cardiol 2009;54:293-302.
JUPITER - Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. N Engl J Med 2008;359:2195-207.
KAPS - Kuopio Atherosclerosis Prevention Study: Circulation 1995;92:1758-64.
LCAS - Lipoprotein and Coronary Atherosclerosis Study: Am J Cardiol 1997;80:278-86.
L-CAD - Lipid-Coronary Artery Disease Study: Am J Cardiol 2000;86:1293-8.
LIPID - Long-term Intervention with Pravastatin in Ischaemic Disease: N Engl J Med 1998;339:1349-57.
LIPS - Lescol Intervention Prevention Study: JAMA 2002;3215-22.
MAAS - Multicentre Anti-Atheroma Study: Lancet 1994;344:633-8.
MARS - Monitored Atherosclerosis Regression Study: Ann Intern Med 1993;119:969-76.
METEOR - Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin: JAMA 2007;297:1344-53.
MIRACL - Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering: JAMA 2001;285:1711-8.
PLAC-I - Pravastatin Limitation of Atherosclerosis in the Coronary arteries (PLAC-I): J Am Coll Cardiol 1995;26:1133-9.
PLAC-II - Pravastatin Limitation of Atherosclerosis in the Carotid arteries. Am J Cardiol 1995;75:455-9.
PROSPER - Prevention of First Stroke: Lancet 2002;360:1623-30.
PROVE-IT - Pravastatin or Atorvastatin Evaluation and Infection Therapy: New Engl J Med 2004;350 (early release).
REGRESS - Regression Growth Evaluation Study: Circulation 1995;91:2528-40.
REVERSAL - Reversal of Atherosclerosis with Aggressive Lipid Lowering. JAMA 2004;291:1071-80.
SCAT - Simvastatin/Enalapril Coronary Atherosclerosis Trial: Circulation 2000;102:1748-54.
TNT - Treating to New Targets. N Engl J Med 2005;352:1425-35.
TREADMILL - Treatment of Peripheral Atherosclerotic Disease with Moderate or Intensive Lipid Lowering: Creager MA, et al [Abstract].
Presented at the 14th International Symposium on Drugs Affecting Lipid Metabolism, New York, September 9-13, 2001. Mohler E, et al. [Abstract].
Presented at the 75th Scientific Sessions of the American Heart Association, Chicago, November 17-20, 2002.
WOSCOPS - West of Scotland Coronary Prevention Study: N Engl J Med 1995;333:1301-7.
Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making
clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and Internet links in this article were current as of the date of publication.
More. . .
(Detail-Document #280502: Page 9 of 9)
Levels of Evidence differences in transporter and metabolic enzyme

In accordance with the trend towards Evidence-Based functions. Pharmacol Ther 2006;112:71-105.
4. FDA. FDA drug safety communication: important
Medicine, we are citing the LEVEL OF EVIDENCE
safety label changes to cholesterol-lowering statin
for the statements we publish. drugs. February 28, 2012.
Level Definition http://www.fda.gov/Drugs/DrugSafety/ucm293101.ht
A High-quality randomized controlled trial (RCT) m. (Accessed March 16, 2012).
High-quality meta-analysis (quantitative 5. Cohen DE, Anania FA, Chalasani N. An assessment
systematic review) of statin safety by hepatologists. Am J Cardiol
B Nonrandomized clinical trial 2006;97:77C-81C.
Nonquantitative systematic review 6. McKenney JM, Davidson MH, Jacobson TA, Guyton
Lower quality RCT JR. Final conclusions and recommendations of the
Clinical cohort study National Lipid Association Statin Safety Assessment
Case-control study Task Force. Am J Cardiol 2006;97:89C-94C.
Historical control 7. American Gastroenterological Association.
Epidemiologic study American Gastroenterological Association medical
C Consensus position statement: evaluation of liver chemistry
Expert opinion tests. Gastroenterology 2002;123:1364-6.
D Anecdotal evidence 8. Stone NJ, Robinson J, Lichtenstein C, et al. 2013
In vitro or animal study ACC/AHA guideline on the treatment of blood
Adapted from Siwek J, et al. How to write an evidence-based clinical cholesterol to reduce atherosclerotic cardiovascular
review article. Am Fam Physician 2002;65:251-8. risk in adults: a report of the American College of
Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation 2013.
Project Leader in preparation of this PL Detail- (Published ahead of print Nov 12). DOI:
Document: Melanie Cupp, Pharm.D., BCPS 10.1161/01.cir.0000437738.63853.7a.
References
1. PL Detail-Document, Statin Dose Comparison (U.S.).
Pharmacist’s Letter/Prescriber’s Letter. August 2009
(Full update June 2013).
2. PL Detail-Document, Statin Dose Comparison
(Canada). Pharmacist’s Letter/Prescriber’s Letter.
August 2009 (Last modified November 2011).
3. Shitara Y, Sugiyama Y. Pharmacokinetic and
pharmacodynamic alterations of 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors: drug-drug interactions and interindividual
Cite this document as follows: PL Detail-Document, Characteristics of the Various Statins. Pharmacist’s
Letter/Prescriber’s Letter. May 2012.
Evidence and Recommendations You Can Trust…

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Combinationd Single Pill Combination Availability Comments

Combinationd Single Pill Combination Availability Comments

Combinationd Single Pill Combination Availability Comments

Thiazidec plus  Hydrochlorothiazide/amiloride (Novamilor  Spironolactone, amiloride, or triamterene offsets thiazide-induced

Combinationd Single Pill Combination Availability Comments

Aliskiren plus  None  No outcomes data.

Dihydropyridine  None  Additive blood pressure reduction.19

Not Preferred Combinations for Uncomplicated Hypertension

Combinationd Single Pill Combination Availability Comments

Non-  None  Risk of heart block and bradycardia.1

Methyldopa plus  None  Risk of heart block and bradycardia.1

Clonidine plus  None  Risk of heart block and bradycardia.1

Levels of Evidence 4. Beckett NS, Peters R, Fletcher AE, et al. Treatment

Evidence and Recommendations You Can Trust…

Characteristics of the Various Statins

View our helpful PL Chart, Non-Statin Lipid-Lowering Agents

▪ Regresses/slows progression of atherosclerosis (ASAP, ARBITER, REVERSAL).

▪ Unclear benefit in peripheral arterial disease (TREADMILL).

▪ No benefit for early treatment of ACS with 80 mg/day (FLORIDA).

▪ Slows progression of atherosclerosis (METEOR).

Statin Clinical Trials

FATS - Familial Atherosclerosis Treatment Study: N Engl J Med 1990;323:1289-98.

Levels of Evidence differences in transporter and metabolic enzyme

Evidence and Recommendations You Can Trust…

Subscribers to the Letter can get PL Detail-Documents, like this one,

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