Starting Antihypertensive Drug Treatment with Combination Therapy

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3-2021

Starting Antihypertensive Drug Treatment With Combination Therapy

Zhen-Yu Zhang

Yu-Ling Yu

Kei Asayama

Tine W. Hansen

Gladys E. Maestre The University of Texas Rio Grande Valley, [email protected]

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Recommended Citation Zhang Zhen-Yu, Yu Yu-Ling, Asayama Kei, Hansen Tine W., Maestre Gladys E., & Staessen Jan A. (2021). Starting Antihypertensive Drug Treatment With Combination Therapy. Hypertension, 77(3), 788–798. https://doi.org/10.1161/HYPERTENSIONAHA.120.12858

This Article is brought to you for free and open access by the School of Medicine at ScholarWorks @ UTRGV. It has been accepted for inclusion in School of Medicine Publications and Presentations by an authorized administrator of ScholarWorks @ UTRGV. For more information, please contact [email protected], [email protected]. Authors Zhen-Yu Zhang, Yu-Ling Yu, Kei Asayama, Tine W. Hansen, Gladys E. Maestre, and Jan A. Staessen

This article is available at ScholarWorks @ UTRGV: https://scholarworks.utrgv.edu/som_pub/265 Hypertension

Review Starting Antihypertensive Drug Treatment With Combination Therapy

Controversies in Hypertension - Con Side of the Argument Zhen-Yu Zhang , Yu-Ling Yu , Kei Asayama , Tine W. Hansen , Gladys E. Maestre , Jan A. Staessen Key Words: angiotensin-converting enzyme inhibitors ◼ angiotensin-receptor blockers ◼ blood pressure ◼ calcium-channel blockers ◼ diuretics ◼ hypertension ◼ renin

he 2018 European Society of Cardiology/European in Table S1 in the Data Supplement; (2) a PubMed search Society of Hypertension1 and the 2020 International ran on May 5, 2020, without limitations with as search TSociety of Hypertension2 guidelines for the manage- terms in the abstract or title “hypertension” combined ment of hypertension proposed that initial combination with “fixed combination” OR “hypertension” combined Downloaded from http://ahajournals.org by on February 11, 2021 therapy with 2 antihypertensive agents in a single-pill with “single” and “costs”; (3) the placebo-controlled trials combination (SPC) is preferred in most patients in need of antihypertensive drug treatment, as identified from the of blood pressure (BP) lowering treatment and should reference lists of 5 systematic literature reviews,13–17 of replace the long-standing concept of starting treatment which 2 were published by the Blood Pressure Lowering with a single agent, rotating through antihypertensive Trialists’ Collaboration14,16; (4) 3 randomized controlled drug classes, and next moving towards combining drug trials of usual versus intensive BP control18–20; and (5) classes. By moving SPCs forward as the initial BP-lower- the retail costs of antihypertensive drugs on the Belgian ing strategy, the European1 and International2 Societies of market (https://www.bcfi.be). Hypertension Guideline Committees overlooked several principles in hypertension management: (1) understand- TAILORING ANTIHYPERTENSIVE ing the pathophysiology of hypertension; (2) prioritizing evidence from randomized clinical trials above obser- TREATMENT vational studies and expert opinion; and (3) giving con- In the early 1970s, Laragh’s group coined the terms sideration to the cost-effectiveness of antihypertensive low-renin, normal-renin, and high-renin hypertension by drug treatment and the sustainability of health care. This relating plasma renin activity to the daily sodium excre- article addresses these points. Sources of information tion.21 Under normal conditions, plasma renin activity included (1) guidelines issued by European,1,3,4 Ameri- increases with sodium restriction but decreases with can,5–7 International,2,8,9 and British10–12 Expert Commit- higher BP.21 Although an imperfect generalization, low- tees, published between 19998 and 2020,2 summarized renin hypertension is characterized by volume expansion

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article was sent to Morris J. Brown, Guest Editor, for review by expert referees, editorial decision, and final disposition. Correspondence to: Jan A. Staessen, Non-Profit Research Institute, Alliance for the Promotion of Preventive Medicine, Leopoldstraat 59, BE-2800 Mechelen, Belgium. Email [email protected] The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.120.12858. For Sources of Funding and Disclosures, see page 796. © 2021 The Authors. Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. Hypertension is available at www.ahajournals.org/journal/hyp

788 March 2021 Hypertension. 2021;77:789–799. DOI: 10.1161/HYPERTENSIONAHA.120.12858 Review

37 37 38 Hg Hg Hg Hg 789 Hg. but not after 1 after 1 19 1–9 at 1 year, at 1 year, 19 or a substantial a or these numbers these numbers March 2021 March Hg in the control Hg in the control 38 20 Single Drug vs Single Pill Single vs Drug Single patients with a sys- 20 Considering the patients Considering the patients persistence, and safety. persistence, and safety. and in SPRINT (Systolic 44 19 In the Hypertension in the In the Hypertension - Protec Perindopril and the 41,42 Hg (N=4683), respectively. (N=4683),Hg respectively. 37 41,42 these levels were 121.4 mm Hg or higher and an increased car- increased an and higher or Hg Hg (usual treatment). In the type-2 Hg (usual treatment). In the type-2 Hg (intensive treatment) or a systolic Hg (intensive treatment) or a systolic 20 comparing intensive with usual BP and in the Systolic Hypertension in and in the Systolic including exclusively including 38 18–20 the study coordinating office emailed or the study coordinating to 87.0%. The first Medical Research Council Trial Council Research Medical first The remained on a single drug and at 4 years remained on a single - reported on treatment status by randomiza 30 40 38 enrolled adults, but all other recruited older adults, but all other enrolled 41,42 19,20 39 30,31,38,40–43 guidelines. What is the evidence? guidelines. What 10–12 proportion of octogenarians. tion Against Recurrent Stroke Study (age range, not range, (age Study Stroke Recurrent Against tion reported) (8.0%) and 265 (28.0%) of patients randomized to 174 intensive and standard treatment were on monotherapy and at the last visit 184 (8.0%) and 553 (24.0%); in SPRINT (median follow-up, 3.3 years), tion group. In the ACCORD Trial (Action to Control Car- tion group. In the ACCORD Trial diovascular Risk in Diabetes) control, 2 EVIDENCE SUPPORTING SPCS adherence literature on SPCsThe focuses on efficiency, (also known as compliance), Intensive Versus Usual BPIntensive Versus Control Of the 3 trials be extracted. These trials were published from 1985 trials were published These be extracted. until 2008. to 90.0% had attained of patients at 4 years of follow-up, 70.0% defined as a diastolic BP of <90the target BP, mm on remained patients of proportion substantial a Thus, goal BPmonotherapy or reached on a single drug in the 1. placebo-controlled trials listed in Table faxed recommendations for intensification of treatment for intensification of treatment faxed recommendations whenever at a visit a patient to the local investigators, smaller resulting in a substantially was not at goal BP, remaining on monotherapy in proportion of patients placebothe group treatment active the with compared Trial, Council Research Medical the first In 1). (Table (N=4683)136.2and mm In ACCORD follow-up, 4.7 years), (median patients, randomized to active treatment, at 2 years, from 25.8% randomized to active all, Over time, these notions permeated to several, at last follow-up were 493 (10.5%) and 1455 (31.1%), respectively. from 48.0% Blood Pressure Intervention Trial), Intervention Blood Pressure Europe Trial, tolic BPtolic 130of mm to a systolic BPdiovascular risk were randomly assigned target of <120 mm target of <140 mm (N=2174) diabetic patients randomized to intensive and usual (N=2208) BP control in ACCORD, Very Elderly Trial Very year, the achieved systolic BP the achieved averaged 119.3 mm year, on intensive treatment and 133.5 mm group; in SPRINT, (age range, 35–64 years) (age range,

22 35,36 30,31 These These The activ- The 25–27 24 or CCBs. and the 2020 1 29 32 unanimously recommend the recommend unanimously 1–12 The observed benefits were mainly benefits observed The 32 is an indication for TDs and are indications to start BP-loweringindications to start and are 28 guidelines recommend to start antihyper- guidelines recommend 2 The involvement of sympathetic drive and drive sympathetic of involvement The We extracted control rates on monotherapy extracted We 22,23 33,34 as well as the trials of intensive versus usual BP 18–20 supported the use of thiazide-like diuretics, that is, supported the use of thiazide-like diuretics, 13–17 2 ACE inhibitors not only inhibit the generation of active use ACE inhibitors and ARBs in patients with diabetes and βBs (beta-blockers), kidney disease, or chronic control. from the trial reports. confined to thiazide-like diuretics rather than TDs with confined to thiazide-like diuretics rather 0.78; ratio, (odds events cardiac of risk the in reductions P<0.001), and P<0.001), heart failure (odds ratio, 0.57; stroke (odds ratio, 0.82; P=0.016). Placebo-Controlled Trials 1 lists the placebo-controlled the trials from which Table proportion of patients remaining on monotherapy could With as objective to estimate the proportion of patients as objective to estimate the With with hypertension who can be controlled on monotherapy, placebo-controlledthe reviewed we clinical randomized BP-loweringof reviews systematic in listed trials therapies CONTROL RATES ON MONOTHERAPYCONTROL RATES VERSUS COMBINATION THERAPY ACE inhibitors, and ARBs in secondary prevention. angiotensin II, but also the inactivation of the vasodila- compared higher potency their explaining bradykinin, tor with ARBs renin inhibitors and the recommen- and direct dation to prescribe ARBs only in ACE inhibitor-intolerant patients. and is lower in Blacks compared with Whites. compared in Blacks and is lower Society 2020 International The guide- of Hypertension line and its high-renin counterpart by increased peripheral by increased peripheral counterpart and its high-renin resistance, International pathophysiological principles explain why guidelines, why principles explain pathophysiological of the 2018 European with the exception ity of the renin system decreases with advancing age with advancing renin system decreases ity of the indapamide and chlorthalidone, rather than regular TDs indapamide and chlorthalidone, sys- based on a and hydrochlorothiazide), (chlorothiazide involving trials clinical randomized 19 of review tematic 112 113 patients. the renin-angiotensin system in the cardiovascular and the renin-angiotensin system in the its comorbidities and hypertension of complications renal guidelines why clarifies treatment with a diuretic as opposed to an inhibitor of opposed to an inhibitor with a diuretic as treatment vasodilator. system or the renin-angiotensin tensive drug treatment with ACEtensive drug treatment (angiotensin-converting ARBsor inhibitors enzyme) thia- with and 55 age below or dihydropyridine CCBszide diuretics (TDs) (calcium- across patients and in Blacks in older blockers) channel Isolated systolic hypertension, which the adult age range. is not associated with increased in its initial course of the by stiffening caused is but resistance, peripheral large arteries 2021;77:789–799. DOI: 10.1161/HYPERTENSIONAHA.120.12858Hypertension. 2021;77:789–799. Zhang et al et Zhang

Downloaded from http://ahajournals.org by on February 11, 2021 Downloaded from http://ahajournals.org by on February 11, 2021 11, February on by http://ahajournals.org from Downloaded 10110 with olmesartan/amlodipine (dailydoses, 10/5,20/5, randomized inequalproportions tocombinationtherapy ranging from95to120mm with adiastolicBP 790 withitscomponents. of aSPC domized clinicaltrialcomparingtheefficacyandsafety Our extensive literaturereviewrevealedonlyoneran- TrialsRandomized Clinical Zhang etal the UnitedStates. a double-blindtrial,conducted at172 clinical sitesin ine Besylate in Controlling High Blood Pressure) was (Combination of Olmesartan Medoxomil and Amlodip- Table 1. Hypertension inEuropeTrial.; andY, medianoraveragefollow-uponrandomizedtreatment. Study on Cognition and Prognosis Shanghai Trialin the Elderly; STONE, Systolic Hypertension in China Trial; of Nifedipine in the Elderly;Syst-China, Syst-Eur, Systolic Perindopril Protection AgainstRecurrentStrokeStudy;PROP, mg/d);SCOPE, propranolol(upto240 PROGRESS, matching perindopril(4mg/d);PLAC, placebo; PER, Medical Research CouncilTrial inOlderAdults;N,numberofpatientsrandomized; NA,notapplicable;NIF, mg/d);NIT, nifedipine mg/d); (20–60 nitrendipine(10–40 amiloride (25/2.5 mg/d);HYVET, Hypertension in theVery MedicalResearch CouncilTrial Elderly Trial; indapamide (1.5mg/d); MRC1, in Young IND, Adults;MRC2, on first-linemonotherapy. BDF, hydrochlorothiazide/AT indicatesatenolol(50–100mg/d); candesartan(8–16mg/d); bendrofluazide(10mg/d);HTCZ/AM, CAND, mm below 90 only athird (N=2285) hadnomeasurementsofdiastolic BP continuedtofallfor5years.Asreportedinreference 37, inwomenrandomizedtoplacebo toreach itslowestapproximately stablelevel.MeandiastolicBP the entryBP was done by a physician. As a result, it took nearly 9 months for measurements on separate occasions, but to ensure their diagnostic categorization, the third entry BP nursesdoingscreeningdid 2 setsofBP domization (blood pressure eligibility criteria) andthegoalbloodpressure (required decreaseinbloodpressure). In MRC1, cation year cation Trial, publi- 1985 MRC1, 2008 HYVET, 1992 MRC2, RESS, 2001 RESS, PROG 1998 Syst-China, 1996 STONE, 2004 SCOPE, 1997 Syst-Eur, ‡Number ofpatients(percentage)remainingonmonotherapy. §Number ofpatients(percentage)reaching goalbloodpressure †An ellipsisindicatesthatthedatacouldnotbeextracted fromthetrialreport. decreaseinbloodpressureonactivetreatment. *The averageplacebo-corrected Age: averageageatrandomization (age eligibility criterion). Blood pressure: the bloodpressuredatagivenareaverage systolic/diastolic blood pressure at ran- March 2021 - Patients RemainingonFirst-LineDrugTreatment inPlacebo-ControlledRandomizedClinicalTrials 37 38 40 39 31 43 41,42 30 Ref Age, y 35–64 52.0, 83.6, ≥80 65–74 65.7, 65.0, NA 66.4, ≥60 66.4, 60–79 66.4, 70–89 76.4, 70.3, ≥60 45,46 Patients aged18yearsorolder Blood pressure, mmHg Entry (<200/90–109) 161.3/98.2 (≥160/<100) 173.0/90.8 (160–209/<115) 184.7/90.7 144.0/84.0 (NA) 144.0/84.0 (160–219/<95) 170.5/86.0 (160–219/96–124) 168.5/97.7 (160–179/90–99) 164.7/90.4 (160–219/<95) 173.8/85.5 45,46 The Study COACH Goal NA/<90 <150/<80 ↓13.5/6.5* ↓9.5/5.5* NA†‡§ 150–160/ ↓4.9/2.8 ↓13.6/7.0* ↓13.6/7.0* >150/NA <160/<90 >160/>85 ↓20/NA ↓10/NA >150/NA ↓20/NA Hg were Hypertension. 2021;77:789–799. 10.1161/HYPERTENSIONAHA.120.12858 DOI: Hg at any follow-up visit.Follow-up: Dataarethe number ofpatients (percentage) remaining Y 4.9 1.8 5.8 3.9 3.0 2.5 3.6 2.0 Drugs PLAC PLAC IND BDF PROP PLAC PLAC AT HCTZ/AM PER PLAC PLAC PLAC NIT NIF PER PLAC NIT (<140/<90 and <130/<90 mm and<130/<90 (<140/<90 controlmorefrequently moreandachieved BP BP and at each dose, combination therapy reduced stolic BP produced dose-dependentdecreases insystolicanddia- ably, each treatment modality, compared with placebo, (87.1%)and 1689 completedthe8-week trial.Predict- mean age,54.0years;entryBP, 164/102mm (45.8%) were randomized (women, 45.7%; phase, 1940 mg). Of4234patients,whoenteredthe2-weekwashout mg)oramlodipine(510 olmesartan (10,20,or40 mg)ormonotherapywith 10/10,20/10,or40/10 40/5, N 8654 1912 1933 4927 4403 2213 1280 1102 1081 1281 1141 815 845 1253 817 1235 2297 2398 Year 1 Follow-up, numberofpatients(%) … (…)† … (≈39.9) … (≈81.9) … (≈63.1) … (≈89.9) … (≈61.9)

578 (60.4) 832 (72.3) 693 (41.2) 693 (59.0) 1037 Year 2 … (…) (25.8) 196 100 (14.2) … (≈41.9) … (≈77.4) … (≈67.1) … (84.9) … (66.4)

348 (42.9) 348 ≈531 (65.0) … (…) (90.0) ≈998 (88.0) ≈634 584 (62.7) 584 343 (27.8)343 597 (46.5) Hg indiabetic patients) Single DrugvsPill Year 3 … (…) … (≈43.9) … (≈74.3) … (≈68.1) … (≈82.4) … (≈67.8)

203 (30.9) 374 (51.5) 178 (19.2) 385 (39.3) 385 Year ≥4 … (…) … (≈45.9) … (≈72.3) … (≈70.1) … (≈79.9) … (70.4) … (…) … (48.0) … (…) … (62.0) … (…) … (…) … (≈86.0) … (≈87.0) ≈271 (87.0) 58 (36.0) 58 (80.0) ≈150 110 (53.7) 95 (13.9) 216 (30.6) Hg) Review

50 791 45,46 Hg at Results 49 March 2021 March <0.0001). Hg. They were ran- Hg. They Hg at week 32 (end Single Drug vs Single Pill Single vs Drug Single Hg at week 24 (midpoint of phase Hg (end of phase 1), 20.1/10.7 ver- Hg) and 2060Hg) (90.7%) the completed of 796 screened patients, 605 (76.0%) patients, 605 screened (76.0%) of 796 Based on the redefinition of the primary 24 24 the PATHWAY-1 researchers reported the researchers the PATHWAY-1 50 In the double-blind PATHWAY-1 study (Prevention study (Prevention PATHWAY-1 In the double-blind average BP results combining phases 2 and 3 and all were similar across sex, age, and ethnicity strata. The limi- strata. The age, and ethnicity sex, were similar across were like those of the COACHtations of this study trial. - assigned to valsartan/amlodipine/hydrochloro randomly valsartan/hydrochlorothiazide mg, thiazide 320/10/25 or amlo- 320/10 mg, valsartan/amlodipine 320/25 mg, of uptitration with mg 10/25 dipine/hydrochlorothiazide daily SPCsthese once to week 3. Of the from week 1 randomized (53.0%) were screened, 2271 4285 patients age, 53.2 years; mean entry BP, (women, 44.7%; mean 169.9/106.5mm all superior to significantly was therapy Triple trial. 8-week in reducing BPof the dual therapies (P were randomized and 432 (71.4%) completed the completed and 432 (71.4%) were randomized were untreated, 1-year follow-up period. Eligible patients home sys- years, and had a self-measured aged 18 to 79 tolic/diastolic BP of ≥150/≥95 mm 50 to 100 domized to initial monotherapy with losartan to 25 mg/d 12.5 or hydrochlorothiazide mg/d (N=151) to the (switching (N=150), crossing over at 8 weeks treatment alternative monotherapy), or initial combination with losartan 50 to 100 mg/d plus hydrochlorothiazide 12.5 to 25 mg/d (N=304). 2 (weeks 17–32), In phase - hydrochlo and mg 100 losartan received patients all 3 (weeks 33–52), rothiazide 12.5 to 25 mg. In phase could be added to amlodipine with or without doxazosin end point was the change primary The target BP. achieve in the systolic home BPhome (target systolic/diastolic BP >140/>90 prespeci- protocol original The mm Hg). at the end of phase fied the time of the primary end point time all 32 weeks after randomization, at which 2, namely, statistical The therapy. same the receiving were patients and unblind- lock analysis plan, published before the data co-primary end points. ing, introduced 2 hierarchical The first was the reduction in the systolic home first was the reduction The BP averaged over phases 1 and 2, testing for the superiority of co- The monotherapy. over therapy combination initial primary end point, to be tested only if the first hypothesis was confirmed, was the reduction in systolic home BP at receiv- were participants all when point, time a 32, week ing the same treatment. Comparing initial monotherapy therapy (Figure 1), the systolic/ with initial combination diastolic reductions in the home BP were 13.3/6.5 versus 21.9/12.1 mm sus 19.5/10.6 mm 2), 23.6/12.7 versus 22.0/11.9 mm of phase 2), and 24.5/13.9 versus 23.6/13.4 mm week 52 (end of study). By the end of phase 3, over monotherapy and com- of participants in the initial 75% bination therapy groups had attained the target home BP between groups at the end of either with no difference phase 2 or 3. and Treatment of Hypertension With Algorithm-Based With of Hypertension and Treatment Trial), Therapy end points,

49 48 with 24 46 Hg in diabetic Hg or higher). and the post hoc analysis of 47 The systolic/diastolic target BPsystolic/diastolic The was 48 -blocker, or spironolactone. The proportion of or spironolactone. The α-blocker, A third randomized double-blind study evaluated the The Simplified Treatment Intervention to Control Simplified The <140/<90 mm Hg and <130/<90 mm patients. The simplified treatment algorithm consisted patients. The of the following: (1) initial therapy with a low-dose ACE inhibitor/TD or ARB/TD SPC; (2) uptitration of the combination therapy to the highest dose; (3) addition and subsequent uptitration of a CCB; and (4) addition of a βB, target BPpatients achieving at 6 months was higher in (N=802) (N=1246)the control experimental than the 6 months, group (64.7% versus 52.7%; P=0.026). At group were on 82.8% of patients in the experimental no infor- SPCs group. However, and 16.4% in the control mation on BP control beyond 6 months was provided. permission. Copyright ©2017, Wiley. permission. Copyright ©2017, patients with isolated systolic hypertension. After a 1-week single-blind placeboAfter run-in, patients were Systolic home blood pressure (BP)Figure 1. Systolic home blood by and follow-up duration. randomization group bars indicate 95% CI. Patients Dataare means. Vertical points were randomized to initial monotherapy with losartan 50–100 (LOS) (HCTZ) 12.5–25 mg (N=150),mg (N=151) or hydrochlorothiazide to the alternative monotherapy), crossing over at 8 weeks (switching or initial combination treatment with losartan 50–100 mg plus 12.5–25 mg (N=304).hydrochlorothiazide 17– In phase 2 (weeks 32), all patients received losartan 100 mg and hydrochlorothiazide with or 12.5 to 25 mg. In phase 3 (weeks 33–52), amlodipine SBP targetwithout doxazosin added to achieve could be BP. Reproduced from MacDonald et al indicates systolic BP. efficacy and safety of triple therapy with amlodipine/valsar- efficacy and safety hyperten- severe or moderate for tan/hydrochlorothiazide 145/100 mm sion (systolic/diastolic BP, Hypertension Study was a cluster-randomized trial, Hypertension Study was a cluster-randomized Canada and involving 45 family practices in Ontario, by as achieved compared control rates of hypertension group) or (experimental treatment algorithm a simplified guideline Program following the Canadian Hypertension group). (control than the equivalent dose of the single-component drug. than the equivalent dose of the single-component Limitations of the COACH trial were selection of patients the short (45.8% of those screened were randomized), weeks), the highly washout (2 weeks) and follow-up (8 predictable BP results, 2021;77:789–799. DOI: 10.1161/HYPERTENSIONAHA.120.12858Hypertension. 2021;77:789–799. Zhang et al et Zhang

Downloaded from http://ahajournals.org by on February 11, 2021 Downloaded from http://ahajournals.org by on February 11, 2021 11, February on by http://ahajournals.org from Downloaded Review from 2000 SPCs producers,5 SPCs not includeaconflictofintereststatement, directly fundedbythepharmaceuticalindustry, et al by one or more industry employees. The study by Hong these manufacturers,and5 as initialmonotherapy, in twice as many participants therapy achieved target BP studies, cipal limitationsaresummarizedinTable S2.Ofthe10 data sourcesconsulted,themethodsapplied,andprin- identified 10studies, PubMed for publicationswithdiscordantresults.We costs. Inviewofthisexceptional consistency, wesearched ing adherenceandpersistence,loweringhealthcare BP, weremoreefficacious inlowering of SDs, increas- orfreecombinations incomparison withSDs that SPCs, drug companieshavingacommercialinterestinSPCs. 792 until 2020, and 7 published in2011 that they had a retrospective design. A meta-analysis A commondenominatorofallobservationalstudieswas Observational Studies study periods. Zhang etal a conflict of interest. In this article, free SD combinations a conflictofinterest. Inthisarticle,free ported byindustry, inwhich noneoftheauthorsreported of antihypertensivedrugtherapy. supporting aninsightfulratherthanasimplisticinitiation plasma reninactivitytertiles,respectively, hydrochlorothiazide weregreatestinthetopandbottom reductionsinducedbylosartanand trial wasthattheBP the currentdebate,arelevantfindingof PATHWAY-1 combinationtherapy. orfreeSD SPC Inthecontext of of whetherantihypertensivetreatmentwasstartedwith wassimilarirrespective week 24(Figure 1),homeBP Of the12studiesincludedinmeta-analysis, groupsviaimprovedclinicaloutcomes. costs intheSPCs persistence likely contributedtothelowerhealthcare The authorshypothesizedthatimprovedadherenceand 1.1–4.1]). combination groups (pooled riskratio,2.1[CI, groupswastwiceaslikelyinthefreeSD the SPC combinations.Persistencecounterparts onfreeSD in patients compared with their higher in non-naive SPC in patientsnaivetopriorantihypertensivedrugsand14% difference inmedicationpossessionratio,was8%higher combinations.Adherence,measuredasthemean free SD $1357 $778–$1935) (CI, than lowerinfavorofSPCs cause andhypertension-relatedhealthcarecostswas The meandifferenceequivalent SDs. intheannualall- versusfree- taking antihypertensiveagentsasSPCs adherence, andpersistencebetweengroupsofpatients The early literature was almost unanimous in stating 68 52,56–59,61,63 standsout,becauseitwas a publicationnotsup- March 2021 51,64–72 52 73 until2010. ofwhich the principaloutcomemeasures, 7 24 hadoneormoreco-authorsemployedby They concludedthatinitialcombination 51,64–67,69,70 51 51,64–67 summarized12studiespublished 51,64–72 24 53 whereasinfactstartingfrom weredirectlysupported by Itcomparedhealthcarecosts, involvedasubcontractor to publishedbetween2010 51,64,65,67,69 wereco-authored 24 anargument 54,56 52,53,55,57–63 52–63 10were Hypertension. 2021;77:789–799. 10.1161/HYPERTENSIONAHA.120.12858 DOI: 2did 64

+$51 to+$55]). in hypertension-related prescription costs (+$53 [CI, to−$114]),butlargerincreases −$302 [CI, costs ($208 reductions inpost-therapyinitiationall-causemedical patientsshowedgreater room visits(−13.0%).SPC all-cause hospitalizations(−23.0%),andemergency had highermedicationpossessionrates(+11.6%),fewer parts on free SD combinations(N=197parts onfreeSD fared betterovera6-monthperiodthantheircounter- patients(N=382 United StatesshowedthatSPC in the to 2008 from the MarketScan Database 2006 excluded fromthe2011meta-analysis. higher BP being an indication for SPCs ormultiple beinganindicationfor SPCs higher BP treatment, of initiationoradjustment of BP-lowering information ontheseverity of hypertensionatthetime ses didnotaccount.Particularly, most studieshadno to overtandhiddensources ofbias,forwhich analy- retrospective designandwere, therefore,vulnerable agement costsinthe2groups(£192versus£192). £78; P<0.001), whereas drugcostswerehigher (£126 versus versus18 users(N=9929 SD patientscomparedwithfree 2011 werelowerinSPC general-practice, hospitalizationcostsvalidatedupto tions ofSDs, orfreecombina - versusSDs aspects oftheuseSPCs twice theexpense thansinglemedicationusers. incurredmorethan tiple medications,includingSPCs, forTDs.Thus, usersofmul- and$49 forARBs at $438 annual costsforeach medicationclasswereestimated formultiplemedicationusers.The average and $436 users forSD perperson:$199 medications was$336 users. The averageannualtotalcostforantihypertensive usersand6212(55.9%)weremultiplemedication SD Among 10 agentswithinorbetweenclasses. switched BP-lowering combinations,orwho ormultiplefreeSD including SPCs used 2 or more antihypertensive medications each year, tension. Multiplemedicationsuserswerepatientswho women, aged18orolder, whohadadiagnosisofhyper- pertensive drugsamongAmericanmenandnonpregnant Survey data,toassesstheusesandexpenses ofantihy- applied the2014to2015MedicalExpenditurePanel compared withgenericSPCs. However, combinationsweremoreexpensive freeSD hypertensive drugsontheBelgianmarket(Table S3). ure 2), atrendstillvisibleinthe2020retailprizesofanti- were highest,whereasthoseforTDslowest(Fig- comparing classesofmedications,thecostsforARBs tive SPCs, when SPCs werenotgenerically available. when SPCs tive SPCs, had average monthly drug costs similar to the respec- of theselectedpatients,areasonwhythisarticle analyses wereadjustedforthebaselinecharacteristics A study published in 2020 without industry support, All observational reviewed above (TableAll observationalreviewed above S2)hada Several studiesaddressedthehealth-economic P<0.001), resulting in similar mean annual man- 971 hypertensiveadults,4759 (44.1%)were 65–67,70,73 73 Similarly, inastudyconductedUK ortripleversusdualSPCs. 68 665; £62versus£112; 665; Single DrugvsPill 51 SPC patients SPC 375). 72 69 73 When 73 Data The was 476) 66 72 68 72

10110 2 793 and 78 77,79,82 with 72 3 included Admittedly, the Admittedly, March 2021 March published from 77–82 10 Single Drug vs Single Pill Single vs Drug Single 76–82 go as far as stating 1 76 Estimated average Figure 2. Estimated each capita expenses of annual per class (95% CI), expressed medication in US based on the 2014–2015 dollars Survey Panel Medical Expenditure Notes. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin CCB,receptor blocker; calcium-channel diuretics. and TD, thiazide blocker; et al Reproduced from Park permission. Copyright ©2020, Elsevier. permission. Copyright ©2020, 6 were written with direct finan- 82 One might argue that SPCs combining 1,2 36,83 or providing assistance in writing the text, or providing assistance in writing the until 2019, Two of its authors held patents for a combina- of its authors held patents for a Two To permeate clinical practice, recommendations To 77 76 47 47 co-authors employed by these manufacturers, involved a for-profit company running the literature involved a for-profit company running search position of βBs as first-line treatment remains a matter of debate, albeit not in the last author’s interpretation of the literature. 1 article’s co-author received research support from a 1 article’s co-author received research company marketing SPCs. cial support from SPC manufacturers, TAKE HOME MESSAGESTAKE 2 lists the major limitations of the recommended Table SPCsusing treatment antihypertensive initiate to policy in most patients. Guidelines of Current Weaknesses only by hypertension guidelines comprehensible Lengthy in primary care and specialists, lead to therapeutic inertia 98-page The fall short of their very reason of existence. 2018 European recommendations Narrative Reviews Of 7 reviews on the use of SPCs, - effec more invariably is therapy combination initial that tive in lowering BP than monotherapy and is, therefore, to sub- cited reference indicated in most patients. The stantiate this claim was a meta-analysis, not of SPCs versus SD but comparing treatment free combinations, strategies consisting of increasing the dose of the first- line antihypertensive agent or adding a second drug class. must excel in simplicity, allowing summarizing key issues allowing summarizing in simplicity, must excel as the AB/CDin a simple mnemonic rule, such algorithm in the 2006 British guideline (Figure 3). tion pill (polypill) for the prevention of cardiovascular disease. 2009

66 65–67,73 A fol- 71 to 5 years introducing introducing 64 or prevention or prevention 69,70 44 claims databases do not claims databases do not 74 and out-of-pocket costs. and out-of-pocket 75 or when 2 or more SDs were prescribed, 73 is an ambiguous concept. Although there is there is is an ambiguous concept. Although 44 low-up duration ranging from 6 months moderate association between claims for filled pre- moderate association between claims scriptions and measured drug levels of adverse health outcomes, is not representative of the life course of hyperten- is not representative of the life in outcomes health adverse measured study No sion. between S2). Transitions a prospective manner (Table health states applied in Markov modeling were not directly measured, but extrapolated, indicating selection bias in the patients being pre- being patients the in bias selection indicating scribed SPCs versus free SD combinations or in data databases by researchers. from the claims extraction an objective Medication possession rate, although closed pharmacy measure, but only in settings with a system, drugs, or on the patients’ health insurance status as status as drugs, or on the patients’ health insurance costs and adherence determinant of the out-of-pocket S2). Data on health behaviors, patients’ lifestyle, (Table were unavailable. and use of over-the-counter drugs imbalance In several analyses, there was a remarkable between SPC and free SD combination users, probabilities of nonadherence were multiplicative, not not multiplicative, were nonadherence of probabilities the claims data used for the additive. Furthermore, health-economic analyses were collected for payment A diagnostic code purposes rather than for research. on a medical claim is no proof for the presence of disease, because diagnoses might be incorrectly coded an a rule-out criterion rather than as or included as studies health-economic reviewed All disease. actual disregard- costs, care health direct for accounted only ing patient values, arbitrariness in selecting data sources best fitting the arbitrariness in selecting data sources best fitting the hypothesis to be proven. ensure that the medication was taken as prescribed. as prescribed. ensure that the medication was taken information from claims databases disfavors Moreover, SDfree publica- their in because combinations, drug tions investigators selected the SD with the worse adherence, 2021;77:789–799. DOI: 10.1161/HYPERTENSIONAHA.120.12858Hypertension. 2021;77:789–799. Zhang et al et Zhang

Downloaded from http://ahajournals.org by on February 11, 2021 Downloaded from http://ahajournals.org by on February 11, 2021 11, February on by http://ahajournals.org from Downloaded Review guideline 794 ologic insights, but in line with the older literature high-renin hypertensivepatientsinlinewithpathophysi- Belgium (www.bcfi.be) mightallowinitiatingtreatmentin a Zhang etal Table 2. gle-pill combinations. blood pressure;RCT, sin- singledrugs;andSPCs, randomizedclinicaltrial;SDs, Ease ofuse SPCs Components of Health carecosts Sponsors studies Observational RCTs Issue -blockers; ACEI, angiotensin-convertingenzymeinhibitors;BP,βB indicates-blockers; ACEI, B and an ACE inhibitor,βB andanACE asforinstancemarketedin March 2021 1–12 Take HomeMessages supports this combination for BP lowering. supports this combination for BP dosing andotheradministrationcharacteristics. side-effects andlong-termtoxicities overfrequencyof the day. Patientswithchronic diseasevalueminimizing drug classesandinspreadingdosingofdrugsover lack flexibilityincombininganddosingindividual SPCs arenotguideline-endorsed. bining aβBandanACEI com- be giventothelong-actingchlorthalidone. SPCs ing hydrochlorothiazide, whereaspreferenceshould isoverwhelminglytheshort-act- The diureticinSPCs all healthcarecosts. donotreduceover- SPCs priceofsartans; high retail increasedrugcosts,mainlyduetothe Use ofSPCs results intheliterature. andthecompleteabsenceofdissonant ence toSDs, health-economic analyses,definitionsofnonadher- sourcesinforming explaining biasinchoosing data sponsoredalmostallstudies, Manufacturers ofSPCs such asfatigueorhypotension,areunder-reported. drug class,butarevaguerandmoredifficulttopick up, adverseeffectscannotbeassociatedwitha of SPCs, Inretrospectiveobservationalstudies ment withSPCs. antihypertensive treat- tional recommendationstostart source ofinformationsupportingEuropeanandInterna- tive designandshortduration(<6months),arethemain Short-term observationalstudies,mostwithretrospec- prevention ofcardiovascularendpoints. controlleadstolong-termbenefitinthe that earlyBP The literaturedoesnotsupportthenotion tions ofSDs. thanfreecombina- isnotbettercontrolledbySPCs BP available showsthat3monthsafterinitiationoftreatment The evidencecurrently scarceRCT combinations ofSDs. ascomparedwithfree sive drugtreatmentwithSPCs effects, andcost-effectivenessofinitiatingantihyperten- Lack ofRCTs comparingthelong-termefficiency, adverse Summary oftheliterature Hypertension. 2021;77:789–799. 10.1161/HYPERTENSIONAHA.120.12858 DOI: 84 no tute for Health andCare Excellence recommendation in treatmentadvice(Table S1).The 2019NationalInsti- weight tonewevidenceasjustificationforany change guidelines ous recommendationorintroducingnewones.The British sive versionsshouldleadtoremovingoradjustingprevi- time, meaningthatevidencepublishedbetweensucces- recommendations. Guidelinesshouldbeincrementalover ies becomethesourceofinformationinevidence-based first 6 months after starting BP-lowering treatment, first 6monthsafterstarting data wereunavailable. Members weredisappointedthatmorecomprehensive hypertension andtype-2diabetes,buttheCommittee might reducecardiovascularcomplicationsinpeoplewith doses ofmonotherapy. a steeperdoseresponsethanisobservedwithescalating responsestoinitialtreatmentandprovides neity oftheBP inducing vasodilatationanddiuresis,reducestheheteroge- nisms, such asblocking therenin-angiotensinsystemand the combinationofmedicationstargetingmultiplemecha- study stated that there was some limited evidence from a single S2) orsystematic of startingantihypertensivetreatmentwithdualtherapy. evidence todetermineconfidentlythebenefitsorharms of life. However, theyfoundthattherewasnotenough and agreedthatthiscouldsubstantiallyimprovequality benefits ofoptimizingtreatmentforhypertensionearly 1). A post hoc analysis of the ment ofhypertension(Figure 1).Aposthocanalysisthe certainly doesnotapplytothelong-termlife coursetreat- arises whenretrospectiveobservationalstudies potential benefits of their products. However, a problem manufacturershighlightingthe is nothingwronginSPC creating therapeuticinnovation.To remainprofitable,there secondary prevention. Nevertheless, guidelines do support such combination in The 2018Europeanguideline The pharmaceuticalindustryisanimportantmotorin 85 thatinitialdualtherapy, comparedwithplacebo, 10–12 areexemplary inthisrespect,givinggreat 51 ornarrative Ltd. Publishing Group Copyright ©2020,BMJ Stroke Association Primary CareCardiovascularSociety, The UK, HEART Society, DiabetesUK, Cardiac Society, BritishHypertension rule.ReproducedfromBritish the AB/CD action shouldbecombinedaccordingto First-linedrugswithdifferentmodesof drugs. combining bloodpressure-lowering Figure 3.Recommendationfor 1 Whereas thismightbetrueduring 11 The Committeediscussedthe 76–82 1 went on proposing that wentonproposingthat reviewsofsuch stud- Single DrugvsPill 10 withpermission. 52–72 50,86 (Table this this 11 11

Review 795 87, and 87, 128, and128, € € 72, 72, € 107, 107, March 2021 March € 44, € Single Drug vs Single Pill Single vs Drug Single 85, 38, Third, titrate each drug to titrate each Third, € 94,95 19, an important research issue is to an important research 11 3592 patients with uncomplicated hypertension with uncomplicated 3592 patients 71 None of the trials of SPCsof of the trials None end point.cardiovascular a had 141. Giving that one-third of the patients started on anti- 141. Giving that one-third of the patients 107, respectively, if the drug with the lowest retail prize if the drug with the lowest respectively, 107, € by a SD,hypertensive therapy can be controlled the poten- are huge, iftial savings for the Belgian health insurance dual SPCs.patients would no longer be started on € expense annual corresponding the prescribed; be would for the lowest-cost SPC with valsartan/hydrochlorothiazide, valsartan/amlodipine, and olmesartan/hydrochlorothiazide, to € amounts olmesartan/amlodipine were followed up for 5 years. Physicians were random- Physicians were up for 5 years. were followed software module expenditure out-of-pocket ized to an and costs for out-of-reimbursement alerts provided that In the therapy and control. TDs as first-line recommended there was a significant increase in theintervention group, in newly treated patients (26.6% versusprescription of TDs were already treated, older patients patients 19.8%). For these find- to a TD. Translating less likely to be switched on S3), starting a patient (Table context ings to the Belgian treatment with chlorthalidone, monotherapy with low-dose perindopril, valsartan, or olmesartanbisoprolol, amlodipine, of € entails an annual cost Rational Use of SPCs therapy in proposed that starting antihypertensive We based onmight be hypertensive patients treatment-naive First, use antihypertensive drugs simple principles. a few action in line with the AB/CD modes of with different algorithm (Figure 3). Second, use antihypertensive agents on their molecularwith a long duration of action based than extended- structure, so-called forgiving drugs, rather release dosage formulations. - primary care prac 76 trial involving cluster-randomized tices, mount outcome-driven randomized clinical trials to delineate mightwho of hypertensive patients subgroups particular Furthermore, compared benefit from starting dual therapy. the highest dose that does not produce adverse effects. adverse effects. the highest dose that does not produce include a thiazide in the drug combination. Finally, Fourth, found by rotatingonce the right combination has been through and combining drug classes as well as the timing of dosing, stimulate adherence by reducing the pill load by prescribing SPCs 2 or 3 antihyperten- including sive agents in adjustable doses. Initiating antihypertensive drug treatment with SDs overcomes the inflexibility of SPCs of the SD in titrating the doses components and the timing of their administration, for instance to prevent nocturnal diuresis or hypotension. In line with the above proposal, in Japan, only one triple-drug SPC is being marketed (telmisartan/amlodipine/hydrochlorothiazide 80/5/12.5 be prescribed after 8 weeks mg). It can only of successful treatment with its components given as dual SPCs plus one SD or as free 3-drug SD combinations In line with the 2019 National Institute for Health and Care Excellence guideline,

87 92 19 88,89 reviewed Moreover, Moreover, 90 Societies of 2 payers, doc- 51–72 93 In a Canadiana In 71 would increase the 7 but a literature review 91 a substantial proportion Preferences varied widely, Preferences 92 and International 1 30,31,37–43 and observational studies and observational In needy patients, out-of-pocket costs are In needy patients, out-of-pocket 20 45,46,48–50 Hg was achieved by monotherapy in aboutHg was achieved one-third of In an era of epidemiological transition, tors, and patients should join forces to keep health careforces to keep health should join and patients tors, sustainable in aging populations. In the placebo-controlled 1), outcome trials (Table of hypertensive patients could be controlled on a single entry and target BPs the these tri- in Arguably, drug. als were higher than those currently proposed. However, mutatis mutandis, lower BP antihyperten- levels, at which sive drug treatment should be initiated, highlighting the need to elicit individual patient preferences, highlighting the need to elicit individual when decisions about are of medications dosing schemes adverse eventsmade, certainly in the light of the potential the advice to initiate of SPCs as mentioned before. Finally, antihypertensive drug therapy with SPCs also goes against pathophysiological principles supporting the use of TDs in and older patients and thelow-renin hypertension, Blacks use vasodilators (ACE inhibitors, ARBs, or CCBs) in high- renin patients or younger individuals (Figure 3). Furthermore, the European Furthermore, trials The with as search terms “preference” AND terms “preference” with as search “patient” AND “pills” did ran on October 20, 2020, with no limitations, or “SPC”, 46among the article yield any not trans- directly hits that for SPCspreference pri- into in patient convenience lated As a corollary, mary or secondary cardiovascular prevention. persons living with HIV treatment-experienced valued mini- over dosing andlong-term toxicities and mizing side-effects administration characteristics. and SPRINT. a major hurdle in long-term adherence. long-term in hurdle major a control rates on monotherapy. BP lowering to <140/90control rates on monotherapy. mm patients randomized to standard treatment in ACCORD Valsartan Antihypertensive Long-Term Use Evaluation Trial Evaluation Trial Use Long-Term Antihypertensive Valsartan notion in the widely promoted did not confirm publi- SPC in BP differences earlier short-term cations that lowering points. cardiovascular end run would reduce over the long in this debate article were generally not powered or hadin this debate article enough to highlight serious adversea duration not long study of As demonstrated by an observational effects. or more and reflecting a real-worldpatients aged 50 years setting, use of SPCs risk of was associated with a greater hypotension than titrated SD free combinations. Hypertension instructions ignored that the association of that the association instructions ignored Hypertension single pharmaceutical formulation maymultiple drugs in a on the pharmacokinetic and pharmacodynamic have effects and may and every individual component properties of each interactions between components. lead to undesired abstraction made of commonly attributable adverse effects, attributable adverse commonly made of abstraction or cough respectively on treatment leg edema for example, with CCBs or ACE many drug-induced com- inhibitors, up, such be picked plaints are vaguer and more difficult to in theory requireas for instance fatigue or dizziness and with the SDrechallenge components of an SPC to identify pills to be taken daily is a central the culprit drug. Fewer concept in the promotion of SPCs, 2021;77:789–799. DOI: 10.1161/HYPERTENSIONAHA.120.12858Hypertension. 2021;77:789–799. Zhang et al et Zhang

Downloaded from http://ahajournals.org by on February 11, 2021 Downloaded from http://ahajournals.org by on February 11, 2021 11, February on by http://ahajournals.org from Downloaded Review sion-associated complications. and betterpreventionofthecardiovascular-renalhyperten- support thesustainabilityofhealthcarebylowerdrugcosts out-of-pocket costs as a factor limiting adherence, antihypertensive drugstoreducehealthcarecosts,decrease should better inform physicians and patients on the costs of to beaddressedbymanufacturers(Table 2).Finally, payers marketed isoverwhelminglyhydrochlorothiazide, anissue 796 REFERENCES None. Disclosures HealthcareCoLtd,Kyoto, Japan. ceived anonbindinggrantfromOMRON The Research InstituteAllianceforthePromotion ofPreventive Medicinere- Source ofFunding Cardiovascular Sciences,UniversityofLeuven, Leuven, Belgium. Research UnitHypertensionandCardiovascularEpidemiology, Departmentof We acknowledge the clerical assistance of Vera De Leebeeck and Renilde Wolfs, Acknowledgment Aging Research, UniversityofTexas RioGrandeValley, Brownsville,TX (G.E.M.). Brownsville, TX (G.E.M.);andAlzheimer´sDiseaseResourceCenterforMinority of HumanGenetics,UniversityTexas RioGrandeValley School ofMedicine, of Denmark,Denmark(T.W.H.); DepartmentofNeurosciencesand Leuven, Belgium(J.A.S.);StenoDiabetesCenterCopenhagen,CapitalRegion T.W.H., J.A.S);BiomedicalSciencesGroup,Faculty ofMedicine,University Mechelen, Belgium(K.A., G.E.M., motion ofPreventive Medicine(APPREMED), of BloodPressure, Sendai,Japan(K.A.);Research InstituteAllianceforthePro- sity School ofMedicine,Tokyo, Japan(K.A.);Tohoku InstituteforManagement (Z.-Y.Z., Y.-L.Y., K.A.);DepartmentofHygieneandPublic Health,Teikyo Univer- Leuven DepartmentofCardiovascularSciences,UniversityLeuven, Belgium From theResearch UnitHypertension and CardiovascularEpidemiology, KU Affiliations ARTICLE INFORMATION interactions. excreted unchanged inurine,therebypreventingdrug-drug but half-life, 8versus>24hours),andisnotmetabolized potent, hasasubstantiallylongerdurationofaction(plasma with hydrochlorothiazide, chlorthalidone is1.5to 2.0 × more Zhang etal

1. 2. 3. 4. 5. 10.1093/eurheartj/ehy339 doi: ment ofarterialhypertension.EurHeartJ.2018;39:3021–3104. Guidelinesforthemanage- Scientific DocumentGroup.2018ESC/ESH Coca A, de Simone G, Dominiczak A, et al; ESC Burnier M, Clement DL, Williams B,ManciaG,Spiering W, AgabitiRoseiE,Azizi M, 2020;75:1334–1357. doi:10.1161/HYPERTENSIONAHA.120.15026 ety of hypertension global hypertension practice guidelines. Schlaich Tomaszewski M,StergiouGS, - M,etal.2020InternationalSoci Unger T, BorghiC,Charchar F, Prabhakaran KhanNA,Poulter D,RamirezA, NR, 2007;28:1462–1536. doi:10.1093/eurheartj/ehm236 2007;28:1462–1536. EurHeartJ. ofCardiology(ESC). andoftheEuropeanSociety sion (ESH) ofHyperten- agement ofarterialhypertensiontheEuropeanSociety for themanagementofarterialhypertension:taskforceman- LaurentS,etal.2007Grassi G,HeagertyAM,KjeldsenSE, Guidelines Mancia G,DeBacker G,DominiczakA, Cifkova R,Fagard R,Germano G, Heart J.2013;34:2159–2219.doi:10.1093/eurheartj/eht151 Eur ofCardiology(ESC). andoftheEuropeanSociety Hypertension (ESH) of for themanagementofarterialhypertension oftheEuropeanSociety guidelines forthemanagementofarterialhypertension:taskforce ESC Christiaens T, CifkovaR,De Backer G,DominiczakA,etal.2013ESH/ Mancia G,Fagard R,NarkiewiczK,Redon J,Zanchetti A,BöhmM, mittee on Prevention, Detection, Evaluation, and Treatment of High Blood Jones DW, MatersonBJ,OparilS,Wright JTJr, etal;JointNational Com- Chobanian AV, Jr, Cushman WC,GreenLA,IzzoJL Black HR, BakrisGL, March 2021 32,95 Unfortunately, currently thediureticinSPCs Hypertension. 71 Hypertension. 2021;77:789–799. 10.1161/HYPERTENSIONAHA.120.12858 DOI: and to andto

22. 21. 20. 19. 18. 16. 15. 14. 13. 12. 11. 10. 17. 9. 8. 6. 7. doi: 10.1038/ki.1974.47 Dunn MJ,Tannen Low-renin hypertension.KidneyInt . 1974;5:317–325. RL. 10.1056/NEJM197203022860901 sterone, heartattack andstroke.NEnglJMed . 1972;286:441–449. doi: Essentialhypertension: renin andaldo- BühlerFR. Krakoff LR, BardRH, BaerL,NewtonMA,GoodwinFT, LaraghJH, Brunner HR, trol. Group. Arandomizedtrialofintensiveversus standardbloodpressurecon- Research etal;The RahmanM,OparilS,Lewis SPRINT CE, DM, Reboussin Wright RoccoMV, JTJr, SinkKM, Whelton Williamson SnyderJK, PK, JD, 10.1056/NEJMoa1001286. in type2diabetesmellitus.NEnglJMed.2010;362:1575–1585. doi: StudyGroup.Effects ofintensiveblood-pressure control The ACCORD 2009;374:525–533. doi:10.1016/S0140-6736(09)61340-4 an open-label randomised trial. with hypertension (Cardio-Sis): Usual versustightcontrolofsystolicbloodpressureinnon-diabeticpatients Mureddu G, Pede S, Maggioni AP, investigators. Lucci D, et al; Cardio-Sis Verdecchia P, StaessenJA, AngeliF, deSimoneG,Achilli A,Ganau doi:10.1093/eurheartj/ehn5752009;30:679–688. tion forpreventionofcongestiveheartfailure:ameta-analysis.EurHeartJ. G.Bloodpressurereductionandrenin-angiotensinsysteminhibi- Reboldi Verdecchia P, AngeliF, Cavallini C,GattobigioR,GentileG,StaessenJA, HJH.0b013e3280bad9b4 angiotensin system.JHypertens.2007;25:951–958. doi:10.1097/ sure dependentandindependenteffects ofagentsthat inhibittherenin- Blood Pressure Lowering Treatment Trialists’ Bloodpres- Collaboration. doi:10.1161/01.HYP.0000174591.42889.a2tension. 2005;46:386–392. cium channel blockers forcoronaryheartdiseaseandstrokeprevention.Hyper- Staessen JA, Porcellati C.Angiotensin-convertingenzymeinhibitorsandcal- Verdecchia P, G, Angeli F, Reboldi GattobigioR, Bentivoglio M, Thijs L, doi:10.1097/HJH.0b013e3280bad9b42003;362:1527–1535. results ofprospectively-designedoverviewsrandomisedtrials.Lancet. ferent blood-pressure-loweringregimensonmajorcardiovascularevents: Blood Pressure Lowering Treatment Trialists’ Effects ofdif- Collaboration. 10.1016/S0140-6736(01)06411-X doi: sure reduction:ameta-analysis.Lancet.2001;358:1305–1315. Staessen JA, Wang Thijs L.Cardiovascularprotectionandbloodpres- JG, ance/CG127. AccessedJanuary23,2021. ods, EvidenceandRecommendations.2011.http://www.nice.org.uk/guid - Management ofPrimaryHypertensioninAdults.ClinicalGuideline127.Meth- TheClinical National InstituteforHealthandClinicalExcellence(NICE). www.nice.org.uk/guidance/ng136. AccessedJanuary23,2021. Adults: DiagosisandManagement.NICEGuideline[NG136].2019.https:// Hypertensionin National InstituteforHealthandClinicalExcellence(NICE). hrt.2005.079988. eases inclinicalpractice.Heart.2005(Suppl5):v1-52.doi:10.1136/ guidelines on prevention of cardiovascular dis- 2: Joint British Societies’ Primary CareCardiovascularSociety,UK, The StrokeAssociation.JBS British CardiacSociety, HEART BritishHypertensionSociety, DiabetesUK, 10.1097/00004872-200311000-00002 doi: agement ofhypertension.J Hypertens . 2003;21:1983–1992. statementonman- ofHypertension(ISH) International Society Hypertension Writing Group.2003World HealthOrganization(WHO)/ Whitworth JA; World of HealthOrganization,InternationalSociety Hypertens. 1999;17:151–183. ofHypertensionguidelinesforthemanagement ofhypertension.J Society World HealthOrganization-International Guidelines Subcommittee.1999 J AmCollCardiol.2018;71:e127–e248. doi:10.1016/j.jacc.2017.11.006 ogy/American Heart Association Task Force on Clinical Practice Guidelines. of highbloodpressureinadults:areporttheAmericanCollegeCardiol- guidelinefortheprevention,detection,evaluation, andmanagement PCNA al. 2017ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/ GiddingS,JamersonKA,JonesDW,Dennison HimmelfarbC,DePalma SM, et Jr, AronowWS,CaseyDE CollinsKJ,Whelton CareyRM, PK, 10.1001/jama.2013.284427 8).JAmMedAssoc.2014;311:507–520. doi: National Committee(JNC sure inadults:reportfromthepanelmembersappointedtoEighthJoint 2014 evidence-basedguidelineforthemanagementofhighbloodpres- Handler J,Lackland DT, LeFevre MacKenzie TD,OgedegbeO,etal. ML, James PA, CushmanWC,Dennison-HimmelfarbC, OparilS,CarterBL, 10.1161/01.HYP.0000107251.49515.c2 treatment ofhighbloodpressure. the JointNationalCommitteeonprevention,detection,evaluation,and Pressure Education Program Coordinating Committee. Seventh reportof Pressure. NationalHeart,Lung, andBloodInstitute;NationalHigh N EnglJMed.2015;373:2103–2116. doi:10.1056/NEJMoa1511939 . 2003;42:1206–1252. doi: Hypertension. 2003;42:1206–1252. Single DrugvsPill Lancet. Review 797 Can J Cardiol. March 2021 March Single Drug vs Single Pill Single vs Drug Single . 2007;23:2877–2885. doi: 2007;23:2877–2885. Curr Med Res Opin. . 2007;63:1055–1061. doi: 2007;63:1055–1061. Eur J Clin Pharmacol. Gong L, Zhang W, Zhu Y, Zhu J, Kong D, Pagé V, Ghadirian P, LeLorier J, LeLorier P, Ghadirian V, Pagé D, Zhu J, Kong Zhu Y, W, Gong L, Zhang (STONE). in the elderly J Hypertens. trial of nifedipine Shanghai Hamet P. 1996;14:1237–1245. doi: 10.1097/00004872-199610000-00013 . to medication. N Engl J Med Adherence T. Blaschke Osterberg L, doi: 10.1056/NEJMra050100 2005;353:487–497. combination of J, Heyrman R. The Chrysant SG, S, Lee Melino M, Karki high blood besylate in controlling and amlodipine olmesartan medoxomil pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week Clin Ther. 2008;30:587–604. doi: study. factorial efficacy and safety 10.1016/j.clinthera.2008.04.002 systolic blood pressure reduction with olmes- Jeune S. Effective Mourad JJ, Le data of analysis hoc Post therapy. combination medoxomil/amlodipine artan Clin Drug parallel-group, multicentre study. from a randomized, double-blind, Invest. 2009;29:419–425. doi: 10.2165/00044011-200929060-00005 Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination ther- NJ. Combination Wald DS, Law M, Morris JK, JP, Wald Bestwick in reducing blood pressure: meta-analysis on apy versus monotherapy 42 trials. Am J Med. 2009;122:290–300.11,000 participants from doi: 10.1016/j.amjmed.2008.09.038 SS,Daskalopoulou RR,Quinn K, Dasgupta KB,Zarnke DM,Rabi P, Ravani RD, L, Feldman et al; Canadian Hyperten- Cloutier L, Trudeau Rabkin SW, Education Hypertension Canadian 2014 The Program. Education sion diagnosis, measurement, pressure blood for recommendations Program of hypertension. and treatment of risk, prevention, assessment 2014;30:485–501. doi: 10.1016/j.cjca.2014.02.002 antihyperten- RD.Glazer Triple YT, Chiang Y, Lacourcière DA, Calhoun a ran- sive therapy with amlodipine, valsartan, and hydrochlorothiazide: domized clinical trial. Hypertension. 2009;54:32–39. doi: 10.1161/ HYPERTENSIONAHA.109.131300 M, Cruickshank B, Caulfield G, McInnes JK, TM, Williams MacDonald IS, Mackenzie Salsbury J, Morant S, et al. Monotherapy DJ, Webb Sever P, a (PATHWAY-1): versus dual therapy for the initial treatment of hypertension doi: randomised double-blind controlled trial. BMJ Open. 2015;5:e007645. 10.1136/bmjopen-2015-007645 S. Single-pill vs free-equiva- Sherrill B, Halpern M, Khan S, Zhang J, Panjabi of health care lent combination therapies for hypertension: a meta-analysis costs and adherence. J Clin Hypertens (Greenwich). 2011;13:898–909. doi: 10.1111/j.1751-7176.2011.00550.x Dezii CM. A retrospective study of persistence with single-pill combination hypertension. Manag therapy vs. concurrent two-pill therapy in patients with Care. 2000;10:6–10. Malesker MA, Hilleman DE. fixed- Comparison of amlodipine/valsartan Manag Care. dose combination therapy and conventional therapy. 2010;19:36–42. therapy with AA, Shoheiber O. Adherence to antihypertensive Taylor fixed-dose amlodipine besylate/benazepril HCl versus comparable Congest Heart Fail. 2003;9:324–332. doi: component-based therapy. 10.1111/j.1527-5299.2003.03269.x Shoheiber O. Adherence patterns among patients treated with Gerbino PP, agents. Am J fixed-dose combination versus separate antihypertensive doi: 10.2146/ajhp060434 Health Syst Pharm. 2007;64:1279–1283. K, D, Rottenkolber M, Kostev Hasford J, Schröder-Bernhardi with antihypertensive treatments: results of a 3-year Dietlein G. Persistence study. cohort follow-up 10.1007/s00228-007-0340-2 Schweizer J, Hilsmann U, Neumann G, Handrock R, Klebs S. Efficacy J, Hilsmann U, Neumann G, Handrock Schweizer of valsartan 160/HCTZand safety 25 mg in fixed combination in hypertensive patients not controlled by candesartan 32 mg plus HCTZ 25 combination. free in mg 10.1185/030079907x242539 and modifications R. Treatment Barron JJ, Daniel G, Makin C, Preblick resource use for fixed-dose vs separate-agent antihypertensive regimens. Drug Benefit Trends. 2008;20:226–247. 2nd, Sheng X, Nelson RE,Brixner DI, KC A. Assess- Jackson Keskinaslan - hydrochlo and valsartan among costs and persistence, adherence, of ment rothiazide retrospective cohorts in free-and fixed-dose combinations. Curr 10.1185/03007990802319364 doi: Med Res Opin. 2008;24:2597–2607. in therapy antihypertensive with Compliance CA. Plauschinat M, Dickson the elderly: a comparison of fixed-dose combination amlodipine/benazepril Am J Cardiovasc Drugs. versus component-based free-combination therapy. 2008;8:45–50. 10.2165/00129784-200808010-00006 doi: Medication utilization pat- Hess G, Hill J, Lau H, Dastani H, Chaudhari P. among patients who were terns and hypertension-related expenditures P from fixed-dose to free-combination antihypertensive therapy. switched T. 2008;33:652–666. 47. 57. 43. 44. 45. 50. 51. 52. 53. 54. 55. 56. 58. 59. 61. 46. 48. 49. 60.

Circulation. . 2001;358:1033–1041. doi: 2001;358:1033–1041. Lancet. . 1998;16(12J Hypertens. doi: 1):1823–1829. pt Julius S. Interaction between renin and the autonomic nervous sys- nervous autonomic the and renin between Interaction S. Julius Am Heart J. 1988;116(2tem in hypertension. 2):611–616. doi: pt 10.1016/0002-8703(88)90559-5 M, Cruickshank Morant S, Caulfield DJ, JK, Webb B, Williams MacDonald TM, IS,al; British Hypertension S, et Mackenzie Padmanabhan I, Sever P, Ford of Hypertension with Treatment and Society of Prevention Programme is superior to Combination therapy (PATHWAY). Therapy Algorithm-based double- hypertension: a of treatment the initial monotherapy for sequential trial. J Am Heart Assoc. 2017;6:e006986.blind randomized controlled doi: 10.1161/JAHA.117.006986 Helmer OM, Judson WE. Metabolic patients with studies on hypertensive not due to hyperaldosternosm. suppressed plasma renin activity doi: 10.1161/01.cir.38.5.965 1968;38:965–976. activ- Marks AD. Suppressed plasma renin BJ, Adlin EV, Channick . 1969;123:131–140.ity in hypertension. Arch Intern Med doi:10.1001/ archinte.1969.00300120019003 of association between plasma-renin Lack Catt KJ. Finnerty FA, Mroczek WJ, hypertension. or stroke in patients with essential and history of heart-attack doi: 10.1016/s0140-6736(73)92069-2 Lancet. 1973;2:464–468. - Isolated systolic hyperten R. Editorial review. Staessen J, Amery A, Fagard sion. J Hypertens. 1990;8:393–405. SHEP of stroke by anti- Group. Prevention Cooperative Research isolated systolic hypertensive drug treatment in older persons with in the Elderly hypertension. Final results of the Systolic Hypertension (SHEP).Program J Am Med Ass. 1991;265:3255–3264.doi:10.1001/ jama.1991.03460240051027 L, Celis H, Arabidze GG, R, Thijs Birkenhäger WH, Fagard Staessen JA, AE, et al. Randomised Fletcher Dollery CT, PW, de Leeuw Bulpitt CJ, double-blind comparison of placeboolder and active treatment for Systolic Hypertension in patients with isolated systolic hypertension. The doi: Investigators. Lancet. 1997;350:757–764. Europe (Syst-Eur) Trial 10.1016/s0140-6736(97)05381-6 JG, Comparison of active Gong L, Liu G, Staessen JA. Liu L, Wang and placebotreatment sys- with isolated in older Chinese patients (Syst-China)tolic hypertension. Systolic Hypertension in China Col- laborativeGroup. 10.1097/00004872-199816120-00016 of thiazide- Cardioprotective effect DW. Wang Chaugai S, Zhao F, Chen P, like diuretics: a meta-analysis. Am J Hypertens. 2015;28:1453–1463. doi: 10.1093/ajh/hpv050 hypertension. G, Birkenhäger WH. Essential J, Bianchi Wang Staessen JA, Lancet. 2003;361:1629–1641. doi: 10.1016/S0140-6736(03)13302-8 Lancet. 2006;368:1449– Oral renin inhibitors. T. Richart Li Y, Staessen JA, 1456. doi: 10.1016/S0140-6736(06)69442-7 Amery A. Secondary pre- L, R, Vanhees Staessen J, Bulpitt C, Cattaert A, Fagard in post-myocardial infarction patients.vention with beta-adrenoceptor blockers Am Heart J. 1982;104:1395–1399. doi: 10.1016/0002-8703(82)90184-3 with beta- JG, R. Treatment Birkenhäger WH, Fagard Wang Staessen JA, of the cardiovascular complications of for the primary prevention blockers hypertension. Eur Heart J. 1999;20:11–24. doi: 10.1053/euhj.1998.1121 MRC trial of treatment of mild Party. Council Working Medical Research doi: 10.1136/hypertension: principal results. Br Med J. 1985;291: 97–104. bmj.291.6488.97 Liu L, Dumitrascu D, AE, Staessen JA, R, Fletcher NS,Beckett Peters Anderson C, et al; HYVET Study Antikainen RL, Nikitin Y, Stoyanovsky V, N of hypertension in patients 80 years of age or older. Group. Treatment Engl J Med. 2008;358:1887–1898. doi: 10.1056/NEJMoa0801369 PROGRESS Collaborative Randomised trial of a perindopril-based Group. blood pressure lowering regimen among 6105 individuals with prior attack. ischaemic transient or stroke council trial of treatment of hyperten- Medical research MRC Party. Working sion in older adults: principal results. Br Med J. 1992;304:405–412. doi: 10.1136/bmj.304.6824.405 D, Hofman A, Olofsson B, Lithell H, Hansson L, Skoog I, Elmfeldt A; SCOPE Zanchetti Study on Cogni- Group. The Study P, Trenkwalder in the Elderly (SCOPE):tion and Prognosis principal results of a random- doi: ized double-blind intervention trial. J Hypertens. 2003;21:875–886. 10.1097/00004872-200305000-00011 D, Hofman A, Olofsson B, Lithell H, Hansson L, Skoog I, Elmfeldt A; SCOPE Zanchetti Study on COgnition The Study Group. P, Trenkwalder in the Elderly (SCOPE);and Prognosis outcomes in patients not receiving add-on therapy after randomization. J Hypertens. 2004;22:1605–1612. doi: 10.1097/01.hjh.0000133730.47372.4c 10.1016/S0140-6736(01)06178-5 27. 37. 35. 24. 25. 26. 28. 29. 31. 32. 33. 34. 41. 42. 23. 30. 36. 38. 39. 40.

2021;77:789–799. DOI: 10.1161/HYPERTENSIONAHA.120.12858Hypertension. 2021;77:789–799. Zhang et al et Zhang

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Zhang etal 69. 68. 66. 65. 64. 63. 62. 71. 75. 70. 73. 72. 76. 78. 74. 67. 77. . 2020;23:394–400. doi:10.1080/13696998.2019.1699799 Med Econ.2020;23:394–400. amlodipine fixed-dosecombinationforhypertensiontreatmentinChina.J Ren M,Xuan D,Lu Y, Fu Y, Xuan J.Economicevaluationofolmesartan/ Cost EffResourAlloc.2015;13:10.doi:10.1186/s12962-015-0036-x sartan, amlodipine,andhydrochlorothiazide againstitsdualcomponents. Economic evaluationofasingle-pilltripleantihypertensivetherapywithval- Stafylas P, Kourlaba G,HatzikouM,GeorgiopoulosD,Sarafidis P, ManiadakisN. doi: 10.1093/ajh/hpt035 bination antihypertensive drug therapy. WangHong SH, J,Tang J.Dynamicviewonaffordabilityoffixed-dosecom- 2012;15:155–165. doi:10.3111/13696998.2011.635229 medication costsinpatientswithhypertensionGermany. JMedEcon. Real-life treatmentpatterns,compliance,persistence,and Schmieder RE. Breitscheidel SandbergA, L,EhlkenB,Kostev K,OberdiekMS, doi:10.3111/13696998.2012.689792 Med Econ.2012;15:897–905. and costsusingsingletabletregimensvsindividualcomponentregimens.J Optimizingadherenceinhypertension:acomparisonofoutcomes Belsey JD. doi: 10.3111/13696998.2011.596873 channel blocker free-combination therapy. dipine single-pill combination versus angiotensin receptor blocker/calcium healthcare resourceutilizationandcostsfornewlyinitiatedvalsartan/amlo- Baser O, Andrews LM, Wang L, Xie L. Comparison of real-world adherence, J MedEcon.2011;14:267–278. doi:10.3111/13696998.2011.570401 lization inhypertensionpatientstreatedwithsingle-pillcombinationtherapy. Fan CP, Yu AP. Copaymentlevel, treatment persistence, andhealthcare uti- Yang W, Fellers Kahler KH, T, OrloffJ,ChangBensimonAG, Wu EQ, doi: Natl MedAssoc. 2009;101:34–39. compliance withantihypertensivetherapyinahigh-riskmedicaidpopulation.J Shaya FT, Frech-Tamas DuD,GbarayorCM, F, LauH,Weir Predictors of MR. 10.1016/j.clinthera.2008.08.010 doi: in aUSmanagedcaredatabase.Clin Ther. 2008;30:1558–1563. ence withmultiple-combinationantihypertensivepharmacotherapies Adher- KeskinaslanJackson A,BrixnerDI. KC 2nd,ShengX,NelsonRE, cardial infarction.JAmMedAssoc.2007;297:177–186. evidence-based pharmacotherapy and long-term mortality after acutemyo- ChongA,AlterDA. Relationshipbetweenadherenceand Rasmussen JN, 2010;26:2065–2076. doi:10.1185/03007995.2010.494462 with singlepillvs.freecombinationantihypertensives.Curr Med Res Opin. Evaluation ofcomplianceandhealthcareutilizationinpatientstreated Yang W, Fellers ChangJ,Kahler KH, T, OrloffJ,Wu EQ,BensimonAG. doi:10.1016/j.sapharm.2019.05.002 Pharm. 2020;16:183–189. of antihypertensivemedicationsamonghypertensiveadults.Res Social Adm Park C,Wang G,NgBP, Ayala C.The Fang usesandexpenses J,DurthalerJM, tension. ImplementSci.2018;13:7. doi:10.1186/s13012-017-0701-x out-of-pocket costsonprimarycareprescribingforuncomplicated hyper- A cluster randomized trial of the effects of showing comparative patient Tamblyn R,Winslade N,QianCJ, MoragaT, HuangA.What isinyourwallet? 10.1007/s11906-012-0280-9 recommended forallpatients?CurrHypertensRep.2012;14:324–332.doi: TaylorCowart JB, AA.Shouldtwo-druginitialtherapyforhypertensionbe 10.2147/JMDH.S122383 doi: making processes.JMultidiscipHealthc.2017;10:101–106. system: howithasinfluencedmedicalpracticeandclinicaldecision- Marzorati C,Pravettoni G.Value asthekeyconceptinhealthcare hypertension. ManagCare.2013;22:45–55. Ram CV. Fixed-dosetriple-combinationtreatmentsinthemanagementof J ClinPract.2009;63:790–798. doi:10.1111/j.1742-1241.2009.01999.x pressure controlandthepotentialroleofsingle-pillcombinationtherapies.Int Issuesinblood Keskinaslan A,KhanZM. OngSH, Burnier M,BrownRE, March 2021 10.1016/s0027-9684(15)30808-7 Am JHypertens. 2013;26:879–887. J MedEcon. 2011;14:576–583. Hypertension. 2021;77:788–799. 10.1161/HYPERTENSIONAHA.121.16672 DOI:

80. 90. 89. 88. 86. 85. 84. 83. 82. 81. 95. 94. 93. 92. 91. 79. 87. trial. with type2diabetesmellitus(theADVANCE trial):arandomisedcontrolled and indapamideonmacrovascularmicrovascularoutcomesinpatients Group.EffectsADVANCE ofafixedcombinationperindopril Collaborative doi: 10.1016/0002-8703(83)90199-0 treated resistanthypertensivepatients.AmHeartJ.1983;106:321–328. comparison betweenpropranololandbendroflumethiazideincaptopril- Staessen J,Fagard R,LijnenP, Verschueren LJ,Amery A. Double-blind doi: 10.1038/s41581-018-0006-6 resistant hypertension:stateoftheart.NatRevNephrol.2018;14:428–441. Wei FF, ZhangZY, HuangQF, StaessenJA. Diagnosisandmanagementof 10.1097/HJH.0000000000002294 Medication adherenceinhypertension.JHypertens.2020;38:579–587. doi: BorghiC,ParatiPoulter G,Pathak A,Toli NR, D,Williams B,Schmieder RE. Cardiovasc Prev.2017;24:265–274. doi:10.1007/s40292-017-0221-4 of hypertension:theroleolmesartan-basedtreatment.HighBloodPress Costa FV. Improvingadherencetotreatmentandreducingeconomic costs 2014;20:93–100. doi:10.18553/jmcp.2014.20.1.93 dose combinationsinhypertensionmanagement.JManagCarePharm. Adherenceandhealthcarecosts withsingle-pillfixed- Hilleman DE. doi:10.4414/smw.2013.13854 Med Wkly.2013;143:w13854. patientsinprimarycare. Swiss zerland: aneconomicevaluationof3,489 ScheunertSchäfer U. Costs of current antihypertensive therapy in Swit- HH, doi: 10.1161/01.HYP.0000103632.19915.0E evidence supportingtheirinterchangeability. Hypertension.2004;43:4–9. Hydrochlorothiazide versus chlorthalidone: Cohen JD. Ernst ME, Carter BL, 1996;1:121–126. pril versusamlodipineonambulatorybloodpressure.BloodPressMonit. Carvajal AR,Guerrero-Pajuelo J.The effects ofmissingadoseenala- Hernández-Hernández R,ArmasdeHernándezMJ,Armas-Padilla MC, Med. 2013;369:448–457. doi:10.1056/NEJMra1201534 Murray CJ, Lopez AD.Measuringtheglobalburdenofdisease.NEnglJ doi:10.1016/j.jval.2020.03.007Value Health.2020;23:851–861. for modernantiretroviraltherapy:resultsofadiscretechoice experiment. HeterogeneouspatientpreferencesAlshareef N,Derrick C,Thielman NM. RegierDA,Ostermann J,Mühlbacher HobbieA,Weinhold A,BrownDS, A, doi:10.2147/ppa.s42012009;3:61–66. amlodipine/atorvastatin fixed combination. considerations in managing cardiovascular risk: focus onsingle pill and Aslam F, HaqueA,Lee V, Foody J.Patient adherenceandpreference icine (Baltimore).2015;94:e2229.doi:10.1097/MD.0000000000002229 (single pill)free-combinations:anestedmatched case-control analysis.Med- Safety offixeddoseantihypertensivedrugcombinationscomparedto Nowak E,HappeA,BougetJ,Paillard F, Vigneau C,ScarabinPY, OgerE. doi:10.1038/ncpcardio1424 2009;6:112–119. opment ofacardiovascularpolypill.Nat Clin Pract Cardiovasc Med. Guglietta A,GuerreroM.Issuestoconsiderinthepharmaceuticaldevel- 10.1111/j.1472-8206.2009.00799.x tion. Present orfuture?FundClinPharmacol.2010;24:37–42.doi: García-Donaire JA, RuilopeLM. Multipleactionfixedcombina- 10.1161/01.HYP.0000236119.96301.f2 doi: in patientsreceivingmonotherapy. Hypertension.2006;48:385–391. tan AntihypertensiveLong-Term UseEvaluation(VALUE) trial:outcomes LaraghJ,Schork MA,HuaTA,Brunner HR, AmerenaJ,etal.The Valsar- Julius S,Weber McInnesGT, MA,KjeldsenSE, Zanchetti A, 10.1161/HYPERTENSIONAHA.108.123455 doi: cluster randomized,controlledtrial.Hypertension.2009;53:646–653. A simplifiedapproach tothetreatmentofuncomplicatedhypertension:a ZouGY,Feldman RD, Vandervoort Wong CJ, MK, NelsonSA,Feagan BG. Lancet. 2007;370:829–840. doi:10.1016/S0140-6736(07)61303-8 Single DrugvsPill Patient PreferAdherence. XXX 799 March 2021 March Single Drug vs Single Pill Single vs Drug Single , Marilucy Lopez-Sublet, Engi Abd El-Hady Algharably, Reinhold Kreutz El-Hady Algharably, Engi Abd , Marilucy Lopez-Sublet, Controversies in Hypertension - Con Side of the Argument - Con in Hypertension Controversies Alexandre Persu Response to Starting Antihypertensive Drug Treatment With Combination Therapy: Therapy: Combination With Drug Treatment to Starting Antihypertensive Response Still, we feel that it does not detract from our plea in favor of the use of combination therapy as first-line our plea in favor of the use of combination that it does not detract from Still, we feel public a more is hypertension with patients most in therapy antihypertensive dual use to recommendation The with hypertension eventually need ≥2 antihypertensive Staessen, two-thirds of patients As indicated by Prof. way as first-line therapy in those patients is the most effective simply think that using single-pill combinations We of public it is the responsibility However, recommendation may benefit the pharma industry. this Admittedly, than it may appear. Staessen’s and our conception is less wide the gap between Prof. Finally, the same as us, patients approach—basically preferred monotherapy is the he focuses on cases in which While Jan Staessen is an internationally recognized expert known for his independent and integer positions. He and his known for his independent internationally recognized expert Jan Staessen is an use of first-line single-pill against the extensive a highly informative, original document coauthors have produced combinations. compared to other supporting the benefit of this with hypertension. Although studies treatment in most patients example, For treatment strategies used in daily practice. this is also the case for other strategies have limitations, by Staes- supported algorithm Health and Care Excellence for Institute in favor of the National the arguments than on rigorously and general principles of pharmacology rest more on clinical expertise sen and colleagues controlled trials. designed randomized health than a trialist’s perspective. blood pressure control. drugs to achieve currently the main barriers to improve blood pressure control worldwide. to overcome poor drug adherence and inertia, the price of single-pill combinations while supporting less expensive, health authorities to negotiate properly generic alternatives. patients with isolated systolic hypertension—we emphasize the big picture inwith mild hypertension, particularly older exceptions. therapy in most patients with hypertension, while mentioning the favor of first-line dual antihypertensive 2021;77:788–799. DOI: 10.1161/HYPERTENSIONAHA.121.16672Hypertension. 2021;77:788–799. Zhang et al et Zhang

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