COMBINED APPROACH FOR THE TREATMENT OF … · COMBINED APPROACH FOR THE TREATMENT OF HYPERTENSION AND DYSLIPIDEMIA Combining hypertension and dyslipidemia treatments – Burnier MEDICOGRAPHIA

Combining hypertension and dyslipidemia treatments – Burnier MEDICOGRAPHIA, Vol 41, No. 3, 2019 105

H ypertension and dyslipidemia are the most prevalent cardiovascularrisk factors in adults. They often coexist in the same patient, resultingin a high or very high risk of developing cardiac, cerebral, or vascular

events due to accelerated atherosclerosis. Despite the availability of very ef-fective therapies to control either hypertension or dyslipidemia, and thus re-duce the global cardiovascular morbidity and mortality, neither hypertensionnor dyslipidemia are adequately controlled in populations. Today, still too manyindividuals are not aware of being hypertensive or dyslipidemic, and amongthose who are aware and treated, less than 50% attain the blood pressure(BP) or the low-density lipoprotein (LDL) levels recommended by internation-al guidelines. Among the many causes of insufficient BP and LDL control isa low adherence and persistence, often attributed to the complexity of pre-scribed regimens. To avoid these problems, the use of single-pill combinationsis strongly recommended for the treatment of hypertension and, to a certaindegree, for the management of dyslipidemia. This approach makes possiblethe simplification of therapy, the reduction in pill burden, and thus improve-ment in adherence and persistence. So far, most single-pill combinations ad-dress only one risk factor. There are, however, good arguments to encouragethe development of new single pills acting across diseases, such as the as-sociation of antihypertensive drugs and lipid-lowering agents in a single tablet.The first combination of this kind associated amlodipine and atorvastatin.Today, several pills combining one or two antihypertensive drugs and a statinhave become available. These combinations should make possible the ad-equate control of more patients with hypertension and dyslipidemia. Simul-taneously treating hypertension and dyslipidemia in patients at risk of cardio-vascular events might help support the observed decline in cardiovascularmortality.

Medicographia. 2019;41:105-111

Introduction

T ogether with smoking, diabetes, and obesity, arterial hypertension and dys-

lipidemia belong to the most prevalent risk factors for the occurrence of car-

diovascular diseases (CVD) in adults. Multiple epidemiological studies have

demonstrated that elevated blood pressure (BP) and high cholesterol levels are

the two major contributing risk factors for the development of myocardial infarc-

tion, heart failure, stroke, and vascular and renal complications. Hypertension and

dyslipidemia frequently coexist in the same patient, and the risk of cardiovascular

Address for correspondence:Prof M. Burnier, HypertensionResearch Foundation, Derrey leMotty 8, 1806 St-Légier – la Chiésaz,Switzerland(email: [email protected])

www.medicographia.com

C OM B I N E D A P P R O A C H F O R T H E T R E AT M E N T O F

H Y P E R T E N S I O N A N D D Y S L I P I D E M I A

European hypertension guide-lines recommend using single-pillcombinations as first-line therapyin order to reduce the pill burdenand to facilitate the patients’ dailydrug intake. In the last guidelinesfrom the United States, the recom-mendation is to dose antihyper-tensive medications once dailyrather than multiple times daily toimprove adherence, and to usecombination pills rather than freeindividual components to improveadherencetoantihypertensive ther-apy.”

‘‘ Why do we need acombined approach for thetreatment of hypertension

and dyslipidemia?

by M. Burnier, Swi tzer land

Michel BURNIER, MD, FASN Hypertension Research FoundationSt-Légier-la-Chiésaz SWITZERLAND



MEDICOGRAPHIA, Vol 41, No. 3, 2019 Combining hypertension and dyslipidemia treatments – Burnier106

complications associated with concomi-

tant hypertension and dyslipidemia is

more multiplicative than just the addi-

tion of the risk of the individual factors.1-3

Today, the prevalence of the coexistence

of hypertension and dyslipidemia ranges

between 15% and 50% depending on

the studied populations and the presence of comorbidities.3

It is particularly high in the elderly.1 In this latter population,

dyslipidemia increases the CVD risk mainly in those patients

with a normal BP, whereas it has less impact on the incidence

of new cardiovascular events in those who are already hy-

pertensive.2

Evidence for a combined management of hypertension and dyslipidemiaLowering BP and cholesterol levels to recommended targets,

as shown in Table I, can reduce cardiovascular events by al-

most 50%.4 Therefore, most recent guidelines for the man-

agement of hypertension in adults recommend not only to

control BP but also to lower serum cholesterol with diet and/

or statins in line with the specific recommendations of the Eu-

ropean Society of Cardiology.5 The benefits of simultaneously

controlling BP and cholesterol levels have been clearly demon-

strated in the original publication of ASCOT (Anglo-Scandina-

vian Cardiac Outcomes Trial),6,7 a randomized controlled tri-

al performed in 19 342 men and women with hypertension,

which included a blood-pressure–lowering arm (BPLA) and

a lipid-lowering arm (LLA). Enrolled patients were aged 40 to

79 years and had at least three other cardiovascular risk fac-

tors than hypertension. In a subanalysis of this trial, atorvastatin

reduced the relative risk of coronary heart disease events by

53% (P<0.0001) among those allocated the amlodipine-perin-

dopril regimen, and by 16% (P, not significant) among those

allocated the atenolol-thiazide regimen (P=0.025 for hetero-

genicity).8 Of note, the rate of fatal myocardial infarction and

nonfatal coronary heart disease and the rate of fatal and non-

fatal stroke were reduced by 48% and 44% respectively in the

amlodipine + perindopril + statin group as compared with the

atenolol + thiazide + placebo group. Recently, the authors

of the trial reported the mortality of the patients in the United

Kingdom (UK) after 16 years of follow-up.9 Interestingly, the

benefits of simultaneous treatment of hypertension and dys-

lipidemia were still present even though the difference between

the two treatment strategies was not significantly different for

total death and cardiovascular deaths. However, there was a

significant difference in stroke death in favor of the amlodipine

group. In patients randomized to the LLA, significantly fewer

cardiovascular deaths (hazard ratio [HR], 0.85 [0.72-0.99];

P=0.0395) occurred among patients assigned to statin (865

deaths) than among those assigned placebo (903 deaths).

In patients not participating in the LLA, there were fewer car-

diovascular deaths (adjusted HR, 0.79 [0.67-0·93]; P=0.0046)

among those assigned to amlodipine-based treatment (745

deaths) than atenolol-based treatment (769 deaths). Thus,

the follow-up of this trial tends to confirm the earlier obser-

vations that both BP-lowering and lipid-lowering treatments

confer long-term cardiovascular benefits. Hence, these data

provide good rationale for combining antihypertensive and

lipid-lowering drugs, possibly in a single pill.

More recently, the results of the HOPE-3 trial (Heart Outcomes

Prevention Evaluation 3), conducted in persons at interme-

diate cardiovascular risk who did not have CVD and who had

SELECTED ABBREVIATIONS AND ACRONYMS

ACCOMPLISH Avoiding Cardiovascular events through COMbination therapy in Patients LIving withSystolic Hypertension

ALLHAT Antihypertensive and Lipid-Lowering treatmentto prevent Heart Attack Trial

ASCOT Anglo-Scandinavian Cardiac Outcomes Trial

BP blood pressure

CVD cardiovascular disease

EURIKA European Study on Cardiovascular Risk

EUROASPIRE III European Action on Secondary and Primary Prevention by Intervention to Reduce Events III

HOPE-3 Heart Outcomes Prevention Evaluation 3 (trial)

LDL-C low-density-lipoprotein cholesterol

PAPA-CAD Perindopril plus Amlodipine in PAtients withCoronary Artery Disease

PURE Prospective Urban Rural Epidemiology (study)

Blood-pressure target

The first objective of treatmentshould be to lower BP to <140/90

mm Hg.

Provided that the treatment is welltolerated, treated BP values should

be targeted to 130/80 mm Hg or

lower in most patients.

In patients <65 years, it is recom-

mended that systolic BP should be

lowered to a BP range of 120 to<130 mm Hg in most patients.

Lipid target

For patients at low-moderate cardiovas-cular risk, statins should be considered to

achieve an LDL-C value of <3.0 mmol/L.

For patients at high cardiovascular risk, statins are recommended to achieve an

LDL-C goal of <2.6 mmol/L, or a reduction

of >50% if the baseline LDL-C is 2.6-5.2

mmol/L.

For patients at very high cardiovascularrisk, statins are recommended to achieve

LDL-C levels of <1.8 mmol/L, or a reduc-

tion of ≥50% if the baseline LDL-C is 1.8-

3.5 mmol/L.

Table I. Target values for blood pressureand lipid control according to the 2018

ESC/ESH guidelines on hypertension man-agement in adults.

Abbreviations: BP, blood pressure; ESC, EuropeanSociety of Cardiology; ESH, European Societyof Hypertension; LDL-C, low-density-lipoprotein

cholesterol.After reference 4: Williams et al. J Hypertens.

2018;36(10):1953-2041. © 2018, Wolters KluwerHealth, Inc. All rights reserved.




a systolic BP of less than 160 mm Hg, further confirmed the

benefits of a combined management of hypertension and dys-

lipidemia as reported in ASCOT.10-12 HOPE-3 was a trial with

a 2-by-2 factorial design, in which 12 705 individuals with no

CVD were randomized to rosuvastatin (10 mg per day) or

placebo and to candesartan (16 mg per day) plus hydro-

chlorothiazide (12.5 mg per day) or placebo. The primary out-

come was the composite of death from cardiovascular caus-

es, nonfatal myocardial infarction, or nonfatal stroke. For the

secondary outcome, heart failure, cardiac arrest, or revascu-

larization were added. The study showed that rosuvastatin

reduced CVD by 26.5%, but that BP lowering (BP reduction

of 6/13 mm Hg) was only associated with a modest 7% rela-

tive risk reduction (RRR) in CVD. However, in a prespecified

subgroup analysis of those with SBP in the highest tertile (>143

mm Hg), there was a 27% RRR in CVD with BP lowering.

The failure of controlling hypertension and dyslipidemia in real lifeIn real life, however, the management of hypertension and dys-

lipidemia suffers from similar problems. Many individuals are

not aware that they have either an elevated BP or a high cho-

lesterol level or both, and among those who know their BP or

cholesterol levels, many are not treat-

ed. Furthermore, when treated, most

of them are not well controlled. In

the EUROASPIRE III survey (Euro-

pean Action on Secondary and Pri-

mary Prevention by Intervention to

Reduce Events III) performed in 2006

and 2007 in 76 centers from 22 Eu-

ropean countries, patients with a clin-

ical diagnosis of coronary heart dis-

ease were identified retrospectively

and then followed-up, interviewed,

and examined at least 6 months af-

ter their event. In this high cardiovas-

cular risk population, 56% had a BP

of 140/90 mm Hg or higher, and 51%

had a serum total cholesterol level

of 4.5 mmol/L or higher.13 However,

only 26.3% of patients using antihy-

pertensive medication had achieved

the BP goal, and 30.6% of patients

on lipid-lowering medication had

reached the total cholesterol goal.14

These figures improved in recent surveys but the rate of con-

trol of both hypertension and dyslipidemia remains globally

unsatisfactory.15 Other data come from the EURIKA survey

(European Study on Cardiovascular Risk), a study conducted

with 7641 outpatients aged at least 50 years, free of clinical

CVD and with at least one major CVD risk factor, selected from

12 European countries in 2009.16,17 In this study, among treat-

ed hypertensives (94.2%), only 38.8% achieved a BP of less

than 140/90 mm Hg, and among treated dyslipidemic patients

(74.4%), 41.2% attained both the total- and LDL-cholesterol

(LDL-C) targets of less than 5 mmol/L and less than 3 mmol/L,

respectively. In EUROASPIRE V, conducted in 27 European

countries, the most recent data show that 42% of patients

had a BP at or above 140/90 mm Hg (≥ 140/85 mm Hg if di-

abetic), 71% had LDL-C at or above 1.8 mmol/L (≥70 mg/dL),

and 29% reported having diabetes.18

The impact of low adherence and persistenceThe poor results measured today in population surveys can-

not be attributed to a lack of drug efficacy. It is well recog-

nized that there is a huge gap between what is observed in

clinical trials, in which BP can be controlled in up to 70% to

80% of patients, and what is observed in real life.19,20 Indeed,

in the ACCOMPLISH trial (Avoiding Cardiovascular events

through COMbination therapy in Patients LIving with Systolic

Hypertension), 74.5% of the patients reached a target BP of

less than 140/90 mm Hg,21 and in the ALLHAT study (Antihy-

pertensive and Lipid-Lowering treatment to prevent Heart At-

tack Trial), the BP target of less than140/90 mm Hg was ob-

tained in more than 60% of patients in all treatment groups.22

However, in the multinational PURE study (Prospective Urban

Rural Epidemiology), only a third of participants achieved BP

control.20 The same is true with lipid-lowering drugs and the

control of dyslipidemia. It is not drug efficacy that poses the

main problem but rather the noninitiation of drug therapy, the

high discontinuation rate, and the low adherence rate (Figure1).23 Indeed, in the United States (US), about one-fourth of hy-

pertensive or dyslipidemic patients never initiate their therapy,24

and close to 50% of them discontinue their treatment at one

time or another, mainly during the first year (about 25%).25,26 In

addition, recent data suggest that high adherence to therapy

Figure 1. Patterns of patient adherence to concomitant hypertension and lipid-loweringtherapy over 3 years. The index date was defined as the date concomitant therapy (ie, second drug) was initiated. Abbreviations: AH, antihypertensive; LL, lipid-lowering.After reference 23: Chapman et al. Arch Intern Med. 2005;165(10):1147-1152. © 2005, American Medical Association.




remains particularly low (around 36%

in 2014) in patients with dyslipidemia

who have not yet experienced a car-

diac event, whereas in patients ini-

tiating treatment after a myocardial

infarction, high adherence was ob-

served in 63.8% of patients.27 Data

suggest that discontinuing lipid-low-

ering treatments may have a major

negative impact on the development

of carotid plaques.28 Data from a

meta-analysis on 376 162 patients

from 20 studies assessing adherence

using prescription-refill frequency for

aspirin, statins, and antihypertensive

drug classes in primary and second-

ary prevention have shown that ad-

herence is below 60% for all drugs in primary prevention and

between 60% and 75% in secondary prevention.29 In a re-

cent survey among Swiss patients with type 2 diabetes and

chronic kidney disease managed by primary care physicians,

only 2.2% of the 1359 patients reached simultaneously the

therapeutic objectives for BP, blood glucose, and lipids, indi-

cating that much work is still needed (Figure 2).30

How to improve the control of hypertension anddyslipidemiaIn order to improve the management of cardiovascular risk

factors such as hypertension, dyslipidemia, or diabetes, re-

duction in the clinical impact of low adherence and persist-

ence has become an important topic of recently published

guidelines.4,31 Thus, European hypertension guidelines rec-

ommend using single-pill combinations as first-line therapy in

order to reduce the pill burden and to facilitate the patients’

daily drug intake.4 In the last guidelines from the US, the rec-

ommendation is to dose antihypertensive medications once

daily rather than multiple times daily to improve adherence,

and to use combination pills rather than free individual com-

ponents to improve adherence to antihypertensive therapy.31

This therapeutic strategy, which had been proposed in 2013

guidelines already, is now well established. Today, its imple-

mentation is favored by the development of many single-pill

combinations containing either two or three drugs belonging

to the antihypertensive classes recommended as first-line ther-

apy, ie, blockers of the renin-angiotensin system, diuretics, and

calcium channel blockers. In the field of dyslipidemia, the most

popular single-pill combination associates a statin and eze-

timibe.

Considering the fact that CVDs are multifactorial with vari-

ous risk factors existing simultaneously and the observation

that hypertension and dyslipidemia frequently coexist, com-

bining antihypertensive and lipid-lowering drugs in a single

tablet appears to be a reasonable therapeutic approach for

the primary or secondary prevention of CVD. This is the case,

for example, in hypertensive patients with a mild elevation of

serum cholesterol and hence a moderate-to-high CV risk. In-

Figure 2. (A) Mean blood pressure andnumber (%) of patients achieving bloodpressure goals according to guidelines

and to the stage of chronic kidneydisease (CKD 0-4) among patients withtype 2 diabetes managed by Swiss pri-

mary care physicians.

(B) Mean low-density lipoprotein-cholesterol levels and number (%) of

patients achieving goals in primary andsecondary prevention according to thestage of CKD 0-4, in the same patient

population. Abbreviations: ADA, American Diabetes

Association; BP, blood pressure; CKD, chronickidney disease; ESH, European Society ofHypertension; LDL, low-density lipoprotein.

After reference 30: Corcillo et al. Swiss MedWkly. 2017;147:w14459. © 2017, Creative

Commons License, https://creativecommons.org/licenses/ by-nc-nd/4.0/legalcode.

A

B

deed, as a principle, it appears more reasonable to reduce

the absolute risk of a future cardiovascular event than to tar-

get an individual risk factor. Based on the results of ASCOT,

the first drug combining an antihypertensive drug and a lipid-

lowering agent was a single pill associating amlodipine and

atorvastatin.32 In clinical studies, this single-pill combination

effectively reduced systolic BP and LDL-C levels, and enabled

more patients to achieve BP and LDL-C goals than single-

agent or placebo therapy.32 In addition, the combination of am-

lodipine with atorvastatin resulted in pharmacodynamic ef-

fects that were not observed with the individual components

or were at least less intensive. This includes improvements in

endothelium-dependent vasodilation, decreased levels of the

inflammatory marker serum C-reactive protein, improved in-

sulin sensitivity, and beneficial effects on atherosclerotic plaque

size and composition.32

Drug adherence to the amlodipine/atorvastatin single pill im-

proved significantly compared with free drugs, but the ame-

lioration in statin adherence appeared to be significant, main-

ly in those patients who were already adherent to atorvastatin

before starting the combination.33 In many countries, the suc-

cess of the single pill of amlodipine and atorvastatin was mit-

igated. Among reasons evoked by physicians for not prescrib-

ing this association, one can cite an unclear definition of the

target population, a lack of flexibility, and the cost. Moreover,

a monotherapy based on a calcium channel blocker does

not control BP in more than 40% of hypertensive patients.

Yet, this does not mean that the concept of combining anti-

hypertensive and lipid-lowering drugs should be abandoned.

It should rather be reconsidered in light of new hypertension

recommendations, avoiding, if possible, the usual criticisms

addressed to single-pill combinations.

Toward new single-pill combinationsAs mentioned previously, new European guidelines for the

treatment of hypertension in adults recommend starting all

new treatments with a dual therapy in a single pill, except in

low-risk grade 1 hypertension (SBP<150 mm Hg) or in very

old (≥80 years) or frail patients, where monotherapy may still

be used. Therefore, new single-pill combinations of antihy-

pertensive and lipid-lowering drugs should now associate at

least two first-line antihypertensive drug classes and one statin

in order to be able to control BP and lipid levels in about

60% of patients. The target population should be primarily

hypertensive patients in primary prevention with a mild to mod-

erate dyslipidemia that does not need high doses of statin but

whose BP can be lowered to target with a dual antihyperten-

sive therapy. Patients with hypertension and stable coronary

heart disease may be another target population. In this per-

spective, a triple combination associating perindopril, amlo-

dipine, and atorvastatin has been launched. This triple com-

bination may have clear advantages in terms of treatment

efficacy but also adherence34,35 and reduction in global cardio-

vascular risk. In a post hoc analysis of the PAPA-CAD non-

interventional trial (Hungarian Perindopril plus Amlodipine in

PAtients with Coronary Artery Disease), in which patients re-

ceived the fixed-dose combination of perindopril/amlodipine

and atorvastatin as a second drug, more patients achieved

BP targets, and metabolic parameters were improved.36

Benefits and risks of triple combinationsActually, besides the ability to improve drug adherence and

persistence, adding a statin to a dual antihypertensive ther-

apy might have additional benefits as discussed above. Thus,

studies have suggested that BP control is improved with

these associations, as observed in the Hungarian study.36 In-

deed, although the issue remains controversial, there is in-

creasing evidence of a positive interaction between statins

and antihypertensive drugs leading to a slightly greater de-

crease in BP when the two therapeutic approaches are com-

bined.37-39

A priori, through their positive impact on adherence and per-

sistence, single pills associating antihypertensive and lipid-

lowering drugs should have a major impact on the incidence

of cardiovascular events and on the cost-effectiveness of

treatments. Today, this has not been formally demonstrated

in prospective randomized trials, but post hoc analyses of

published studies suggest that this approach may indeed

be cost effective. A post hoc analysis of the ASCOT trial has

evaluated the cost effectiveness of the different strategies

applied in the trial.40

Using a Markov model, it appeared that the combination of

amlodipine-based therapy and atorvastatin is cost effective in

patients with hypertension and three or more additional risk

factors according to the UK or Swedish societal perspective.

Moreover, in patients who occasionally miss doses of anti-

hypertensives, modest differences in the rate of loss of an-

tihypertensive effect after treatment interruption may have a

clinically relevant impact on BP reduction and CVD risk.41

Are there any risks associated with the use of triple combi-

nations including antihypertensive and lipid-lowering drugs?

In theory, there should not be more side effects with a triple

combination than with three free drugs of the same com-

pounds, provided drugs are taken regularly as prescribed. A

frequent argument against single-pill combinations is that it

might be more difficult to attribute new side effects to the right

component of the combination. In fact, this is rarely the case

because the side effects of statins, amlodipine, and block-

ers of the renin-angiotensin system are well-known after more

than 20 years of use. Therefore, side effects are easily recog-

nized. The flexibility of the treatment, another potential con-

cern, can be improved with an adequate choice of dosing pos-

sibilities and defining a precise stepped-care approach, which

takes into account the need to control hypertension, as well

as dyslipidemia. One of the issues is probably linked to even-

tual discontinuations for any reasons. In that case, the pa-







References1. Kostis JB. The importance of managing hypertension and dyslipidemia to de-

crease cardiovascular disease. Cardiovasc Drugs Ther. 2007;21(4):297-309.

2. Wong ND, Lopez VA, Roberts CS, et al. Combined association of lipids and

blood pressure in relation to incident cardiovascular disease in the elderly: the

cardiovascular health study. Am J Hypertens. 2010;23(2):161-167.

3. Wong ND, Lopez V, Tang S, Williams GR. Prevalence, treatment, and control

of combined hypertension and hypercholesterolemia in the United States. AmJ Cardiol. 2006;98(2):204-208.

4. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the

management of arterial hypertension: The Task Force for the Management of

Arterial Hypertension of the European Society of Cardiology and the European

Society of Hypertension. J Hypertens. 2018;36(10):1953-2041.

5. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the

management of dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058.

6. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events

with atorvastatin in hypertensive patients who have average or lower-than-av-

erage cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes

Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled

trial. Lancet. 2003;361(9364):1149-1158.

7. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. 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(9489):895-906.

8. Sever P, Dahlöf B, Poulter N, et al; ASCOT Steering Committee Members. Po-

tential synergy between lipid-lowering and blood-pressure-lowering in the An-

glo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2006;27(24):2982-2988.

9. Gupta A, Mackay J, Whitehouse A, et al. Long-term mortality after blood pres-

sure-lowering and lipid-lowering treatment in patients with hypertension in the

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year

follow-up results of a randomised factorial trial. Lancet (London, England). 2018;

392(10153):1127-1137.

10. Lonn EM, Bosch J, Lopez-Jaramillo P, et al. Blood-pressure lowering in inter-

mediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374

(21):2009-2020.

11. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk

persons without cardiovascular disease. N Engl J Med. 2016;374(21):2021-

2031.

12. Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in per-

sons without cardiovascular disease. N Engl J Med. 2016;374(21):2032-2043.

13. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. EURO-

ASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug

therapies in coronary patients from 22 European countries. Eur J CardiovascPrev Rehabil. 2009;16(2):121-137.

14. Kotseva K, Wood D, De Backer G, et al. EUROASPIRE III. Management of car-

diovascular risk factors in asymptomatic high-risk patients in general practice:

cross-sectional survey in 12 European countries. Eur J Cardiovasc Prev Re-habil. 2010;17(5):530-540.

15. Kotseva K, De Bacquer D, Jennings C, et al. Time trends in lifestyle, risk factor

control, and use of evidence-based medications in patients with coronary heart

disease in Europe: results from 3 EUROASPIRE surveys, 1999-2013. GlobHeart. 2017;12(4):315-322 e313.

16. Banegas JR, Lopez-Garcia E, Dallongeville J, et al. Achievement of treatment

goals for primary prevention of cardiovascular disease in clinical practice across

Europe: the EURIKA study. Eur Heart J. 2011;32(17):2143-2152.

17. Halcox JP, Banegas JR, Roy C, et al. Prevalence and treatment of atherogenic

dyslipidemia in the primary prevention of cardiovascular disease in Europe:

EURIKA, a cross-sectional observational study. BMC Cardiovasc Disord. 2017;

17(1):160.

18. Kotseva K, De Backer G, De Baquer D, et al; EUROASPIRE Investigators. Life-

style and impact on cardiovascular risk factor control in coronary patients across

27 countries: Results from the European Society of Cardiology ESC-EORP

EUROASPIRE V registry. Eur J Prev Cardiol. 2019;26(8):824-835.

19. Burnier M. Blood pressure control and the implementation of guidelines in

clinical practice: can we fill the gap? J Hypertens. 2002;20(7):1251-1253.

20. Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and

control of hypertension in rural and urban communities in high-, middle-, and

low-income countries. JAMA. 2013;310(9):959-968.

21. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hy-

drochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;

359(23):2417-2428.

22. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Reseach

Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart

Attack Trial. Major outcomes in high-risk hypertensive patients randomized to

angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuret-

ic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack

Trial (ALLHAT). JAMA. 2002;288(23):2981-2997.

23. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with anti-

hypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165(10):1147-

1152.

24. Fischer MA, Choudhry NK, Brill G, et al. Trouble getting started: predictors of pri-

mary medication nonadherence. Am J Med. 2011;124(11):1081.e9-1081.e22.

25. Shani M, Lustman A, Vinker S. Adherence to oral antihypertensive medications,

are all medications equal? J Clin Hypertens (Greenwich). 2019;21(2):243-248.

26. Tajeu GS, Kent ST, Kronish IM, et al. Trends in antihypertensive medication dis-

continuation and low adherence among Medicare beneficiaries initiating treat-

ment from 2007 to 2012. Hypertension. 2016;68(3):565-575.

27. Colantonio LD, Rosenson RS, Deng L, et al. Adherence to statin therapy among

US adults between 2007 and 2014. J Am Heart Assoc. 2019;8(1):e010376.

28. Du R, Zhao XQ, Cai J, Cuui B, Wu HM, Ye P. Changes in carotid plaque tissue

composition in subjects who continued and discontinued statin therapy. J ClinLipidol. 2016;10(3):587-593.

29. Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardio-

vascular disease: meta-analysis on 376,162 patients. Am J Med. 2012;125(9):

882-887.e881.

30. Corcillo A, Pivin E, Lalubin F, Pitteloud N, Burnier M, Zanchi A. Glycaemic, blood

pressure and lipid goal attainment and chronic kidney disease stage of type 2

diabetic patients treated in primary care practices. Swiss Med Wkly. 2017;147:

w14459.

31. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/

AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection,

evaluation, and management of high blood pressure in adults: a report of the

American College of Cardiology/American Heart Association Task Force on

Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248.

32. Curran MP. Amlodipine/atorvastatin: a review of its use in the treatment of hy-

pertension and dyslipidaemia and the prevention of cardiovascular disease.

Drugs. 2010;70(2):191-213.

33. Schaffer AL, Buckley NA, Pearson SA. Who benefits from fixed-dose combi-

nations? Two-year statin adherence trajectories in initiators of combined amlo-

dipine/atorvastatin therapy. Pharmacoepidemiol Drug Saf. 2017;26(12):1465-

1473.

34. Selak V, Elley CR, Bullen C, et al. Effect of fixed dose combination treatment on

adherence and risk factor control among patients at high risk of cardiovascu-

tient will interrupt the therapy of two risk factors at once, which

may lead to a rebound effect and the occurrence of a car-

diovascular event.

ConclusionThe majority of cardiovascular events occur in patients with

modest increases in BP and/or serum cholesterol in combi-

nation with other risk factors, such as smoking, diabetes,

and obesity. In the last 10 years, cardiovascular mortality has

decreased continuously in developed countries.42 The most

effective means of reducing CV risk and cardiovascular mor-

tality further is to manage simultaneously all risk factors. The

development of new, effective, and well-tolerated single pills

combining two antihypertensive classes and one lipid-low-

ering drug will provide additional opportunities to increase the

percentage of patients achieving their BP and LDL-C treat-

ment targets and thereby helps support the observed decline

in cardiovascular mortality. n

lar disease: randomised controlled trial in primary care. BMJ. 2014;348:g3318.

35. Thom S, Poulter N, Field J, et al; UMPIRE Collaborative Group. Effects of a

fixed-dose combination strategy on adherence and risk factors in patients with

or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013;310

(9):918-929.

36. Dezsi CA. Treatment with triple combination of atorvastatin, perindopril, and

amlodipine in patients with stable coronary artery disease: a subgroup analy-

sis from the PAPA-CAD study. J Int Med Res. 2018;46(5):1902-1909.

37. Briasoulis A, Agarwal V, Valachis A, Messerli FH. Antihypertensive effects of

statins: a meta-analysis of prospective controlled studies. J Clin Hypertens(Greenwich). 2013;15(5):310-320.

38. Strazzullo P, Kerry SM, Barbato A, Versiero M, D'Elia L, Cappuccio FP. Do

statins reduce blood pressure?: a meta-analysis of randomized, controlled tri-

als. Hypertension. 2007;49(4):792-798.

39. You T, Liu XG, Hou XD, et al. Effect of statins on blood pressure: analysis on

adverse events released by FDA. Clin Exp Hypertens. 2017;39(4):325-329.

40. Lindgren P, Buxton M, Kahan T, et al. The lifetime cost effectiveness of amlo-

dipine-based therapy plus atorvastatin compared with atenolol plus atorvas-

tatin, amlodipine-based therapy alone and atenolol-based therapy alone: re-

sults from ASCOT1. Pharmacoeconomics. 2009;27(3):221-230.

41. Lowy A, Munk VC, Ong SH, et al. Effects on blood pressure and cardiovascu-

lar risk of variations in patients’ adherence to prescribed antihypertensive drugs:

role of duration of drug action. Int J Clin Pract. 2011;65(1):41-53.

42. Wilson L, Bhatnagar P, Townsend N. Comparing trends in mortality from car-

diovascular disease and cancer in the United Kingdom, 1983-2013: joinpoint

regression analysis. Popul Health Metr. 2017;15(1):23.




Keywords: adherence; blood pressure; interaction; lipid; persistence; single-pill combination; target

Documents

COMBINED APPROACH FOR THE TREATMENT OF … · COMBINED APPROACH FOR THE TREATMENT OF HYPERTENSION AND DYSLIPIDEMIA Combining hypertension and dyslipidemia treatments – Burnier MEDICOGRAPHIA