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MINI-FOCUS ISSUE: CARDIOVASCULAR COMORBIDITIES

STATE-OF-THE-ART REVIEW

The Transition From Hypertensionto Heart Failure

Contemporary Update

Franz H. Messerli, MD,a,b,c Stefano F. Rimoldi, MD,a Sripal Bangalore, MDd

JACC: HEART FAILURE CME/MOC

This article has been selected as the month’s JACC: Heart Failure

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by selecting the JACC Journals CME/MOC tab.

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plications of hypertension in heart failure and associated management

strategies; and 3) select appropriate antihypertensive agents for

From the aDepartment of Cardiology and Clinical Research, Inselspital, Bern

of Cardiology, Mount Sinai Health Medical Center, Icahn School of Medic

Krakow, Poland; and the dLeon H. Charney Division of Cardiology, New York

Dr. Messerli has served as a consultant for Daiichi-Sankyo, Pfizer, Servier, Web

served as a consultant for Servier, Menarini, and Takeda. Dr. Bangalore has

contents of this paper to disclose.

Manuscript received January 7, 2017; revised manuscript received April 19,

patients with hypertension who are at risk for or currently diagnosed

with heart failure.

CME/MOC Editor Disclosure: Editor-in-ChiefChristopherM.O’Connor,MD,

FACC, has received consultant fees/honoraria from AbbVie, Inc., Actelion

Pharmaceuticals Ltd., Bayer, Bristol Myers Squibb, Cardiorentis, Merco &

Co., Inc., ResMed, and Roche Diagnostics; and ownership interest in Bis-

cardia, LLC. Executive Editor Mona Fiuzat, PharmD, FACC, has received

research support from ResMed, Gilead, Critical Diagnostics, Otsuka, and

Roche Diagnostics. Tariq Ahmad, MD, MPH, has received a travel scholar-

ship from Thoratec. Robert Mentz, MD, has received a travel scholarship

from Thoratec; research grants from Gilead; research support from

ResMed, Otsuka, Bristol-Myers Squibb, AstraZeneca, Novartis, and Glaxo-

SmithKline; and travel related to investigator meetings from ResMed,

Bristol-Myers Squibb, AstraZeneca, Novartis, and GlaxoSmithKline. Adam

DeVore, MD, has received research support from the American Heart

Association, Novartis Pharmaceuticals, Thoratec, and Amgen. Abhinav

Sharma, MD, has received support from Bayer-Canadian Cardiovascular

Society,Alberta InnovatesHealthSolution,RocheDiagnostics,andTakeda.

Mitchell Psotka, MD, PhD, and Kishan Parikh, MD, have no relationships

relevant to the contents of this paper to disclose.

Author Disclosures: Dr. Messerli has served as a consultant for Daiichi-

Sankyo, Pfizer, Servier, WebMD, Ipca, ACC, Menarini, and Sandoz.

Dr. Rimoldi has served as a consultant for Servier, Menarini, and Takeda.

Dr. Bangalore has reported that he has no relationships relevant to the

contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC Term of Approval

Issue date: August 2017

Expiration date: July 31, 2018

University Hospital, Bern, Switzerland; bDepartment

ine, New York, New York; cJagiellonian University,

University School of Medicine, New York, New York.

MD, Ipca, ACC, Menarini, and Sandoz. Dr. Rimoldi has

reported that he has no relationships relevant to the

2017, accepted April 19, 2017.

Messerli et al. J A C C : H E A R T F A I L U R E V O L . 5 , N O . 8 , 2 0 1 7

Transition From Hypertension to HF A U G U S T 2 0 1 7 : 5 4 3 – 5 1

544

The Transition From Hyper

tension to Heart Failure

Contemporary Update

Franz H. Messerli, MD,a,b,c Stefano F. Rimoldi, MD,a Sripal Bangalore, MDd

ABSTRACT

Longstanding hypertension ultimately leads to heart failure (HF), and, as a consequence most patients with HF have a

history of hypertension. Conversely, absence of hypertension in middle age is associated with lower risks for incident

HF across the remaining life course. Cardiac remodeling to a predominant pressure overload consists of diastolic

dysfunction and concentric left ventricular (LV) hypertrophy. When pressure overload is sustained, diastolic dysfunction

progresses, filling of the concentric remodeled LV decreases, and HF with preserved ejection fraction ensues. Diastolic

dysfunction and HF with preserved ejection fraction are the most common cardiac complications of hypertension. The end

stage of hypertensive heart disease results from pressure and volume overload and consists of dilated cardiomyopathy

with both diastolic dysfunction and reduced ejection fraction. “Decapitated hypertension” is a term used to describe the

decrease in blood pressure resulting from reduced pump function in HF. Progressive renal failure, another complication

of longstanding hypertension, gives rise to the cardiorenal syndrome (HF and renal failure). The so-called Pickering

syndrome, a clinical entity consisting of flash pulmonary edema and bilateral atheromatous renovascular disease, is a

special form of the cardiorenal syndrome. Revascularization of renal arteries is the treatment of choice. Most

antihypertensive drug classes when used as initial therapy decelerate the transition from hypertension to HF, although

not all of them are equally efficacious. Low-dose, once-daily hydrochlorothiazide should be avoided, but long-acting

thiazide-like diuretics chlorthalidone and indapamide seem to have an edge over other antihypertensive drugs in

preventing HF. (J Am Coll Cardiol HF 2017;5:543–51) © 2017 by the American College of Cardiology Foundation.

M ost longstanding hypertension ultimatelyleads to heart failure (HF) unless thissequence of events is otherwise interrup-

ted by other outcome and, as a consequence, patientswith HF very commonly have a history of hyperten-sion. In the Framingham Heart Study cohort in a totalpopulation of 5,143 subjects, hypertension antedatedthe development of HF in 91% of all newly diagnosedHF patients during up to 20 years of follow-up(mean 14.1 years) (1). Adjusting for age and HF riskfactors, the hazard for developing HF in hypertensivecompared with normotensive subjects in the Fra-mingham Heart Study data was about 2-fold in menand 3-fold in women. Multivariable analyses revealedthat hypertension had a high population-attributablerisk for HF, accounting for 39% of cases in men and59% in women. Among hypertensive subjects,myocardial infarction, diabetes, left ventricular (LV)hypertrophy, and valvular heart disease predictedan increased risk for HF in both sexes. At 80 years ofage, the lifetime risk of HF was about 20% in the Fra-mingham cohort, and this risk doubled for patientswith blood pressure (BP) of 160/100 mm Hg comparedwith those with 140/90 mm Hg (2).

Not surprisingly, prevention of hypertension andother HF risk factors such as obesity and diabetesduring middle age substantially prolongs HF-free

survival. Men and women without hypertension,obesity, or diabetes at 45 years of age lived on average34.7 years and 38.0 years without incident HF, andthey lived on average an additional 3 to 15 yearslonger free of HF than did those with 1, 2, or 3 riskfactors (3). Thus, the absence of hypertension,obesity, and diabetes by 45 and 55 years of age isassociated with up to 86% lower risks for incident HFin men and women across the remaining lifecourse. Importantly, the 22-year follow up of theSHEP (Systolic Hypertension in the Elderly Program)trial documented that, compared with placebo, eachmonth of active chlorthalidone-based antihyperten-sive therapy during the trial period of 4.5 yearswas associated with 1-day prolongation oflife expectancy free from cardiovascular death (4).

PATHOPHYSIOLOGY

In most hypertensive patients, LV diastolic dysfunc-tion is the first discernible manifestation of heartdisease (Figure 1). Cardiac remodeling to a predomi-nant pressure overload consists of concentric LVhypertrophy (increase in cardiac mass at the expenseof chamber volume). In contrast, cardiac remodelingto a predominant volume overload (e.g., obesity,chronic kidney disease, anemia) consists of eccentric

AB BR E V I A T I O N S

AND ACRONYM S

ARAS = atheromatous renal

artery stenosis

ACE = angiotensin-converting

enzyme

ARB = angiotensin receptor

blocker

BP = blood pressure

CCB = calcium-channel blocker

CI = confidence interval

CRS = cardiorenal syndrome

CRT = cardiac

resynchronization therapy

HF = heart failure

HFpEF = heart failure with

preserved ejection fraction

HFrEF = heart failure with

reduced ejection fraction

LV = left ventricular

RR = risk ratio

SBP = systolic blood pressure

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hypertrophy (increase in cardiac mass and chambervolume) (5). When pressure overload is sustained,diastolic dysfunction progresses, the concentricremodeled LV decompensates, and hypertensiveHF with preserved ejection fraction (HFpEF) ensues.In contrast, when volume overload is sustained,LV dilatation progresses, the eccentric remodeledLV decompensates, and HF with reduced ejectionfraction (HFrEF) ensues. The combination of LVhypertrophy with increased levels of biomarkersof subclinical myocardial injury (high-sensitivitycardiac troponin T, N-terminal pro–B-type natriureticpeptide) identifies patients at highest risk for devel-oping symptomatic HF, especially HFrEF (6). Theend stage of hypertensive heart disease, usually theresult of longstanding pressure and volume overload,consists of dilated cardiomyopathy with both dia-stolic dysfunction and reduced ejection fraction.

From a clinical point of view, hypertensive heartdisease can be divided into 4 ascending categories,based on the pathophysiologic and clinical impact ofhypertension on the heart:

De

De

De

De

gree I: Isolated LV diastolic dysfunction with noLV hypertrophy

gree II: LV diastolic dysfunction with concentricLV hypertrophy

gree III: Clinical HF (dyspnea and pulmonaryedema with preserved ejection fraction)

gree IV: Dilated cardiomyopathy with HF andreduced ejection fraction (7)

The categories would indicate that diastolicdysfunction is a much more common complication oflongstanding hypertension than is systolic dysfunc-tion. Patients with HFpEF have more LV hypertrophy,epicardial coronary artery lesions, coronary micro-vascular rarefaction, and myocardial fibrosis than docontrol subjects. Coronary microvascular dysfunctionmay conceivably be the result of a systemic inflam-matory state and oxidative stress accelerated bycomorbidities of HFpEF (8,9). Importantly, isolateddiastolic dysfunction also can trigger pulmonaryedema, as was documented by Gandhi et al. (10). Theyfound LV ejection fraction during an episode of acutehypertensive pulmonary edema to be similar to theone measured after treatment, when the BP had beencontrolled. In these patients systolic BP (SBP) was200 � 26 mm Hg during the initial echocardiographicexamination and reduced to 139 � 17 mm Hg at thetime of the follow-up examination. Thus, a normal LVejection fraction after the treatment of a patient withhypertensive pulmonary edema allows us to concludethat the pulmonary congestion was due to isolated,

transient diastolic dysfunction. Transientsystolic dysfunction with or without mitralregurgitation seemed to be infrequent duringacute episodes in these patients (10).

DECAPITATED HYPERTENSION

In advanced HF, SBP is usually low, even inpatients who were previously hypertensive.This phenomenon is termed “decapitatedhypertension”: patients who are hyperten-sive to begin with progressively developnormal and even low BP as HF becomes moresevere. Severe LV dysfunction can be apowerful antihypertensive mechanism. Thedecrease in SBP results from reduced pumpfunction and fall in cardiac output despite thepresence of compensatory mechanisms suchas peripheral vasoconstriction. Patients withdecapitated hypertension are difficult tomanage because of their inability to tolerateHF medications, most of which tend to lowerBP, such as angiotensin-converting enzyme(ACE) inhibitors or angiotensin receptor

blockers (ARBs), diuretics, and beta-blockers.

This interplay among high BP, hypertensive HF,and dilated cardiomyopathy (i.e., the phenomenon ofdecapitated hypertension) was lucidly discussed byCelia Oakley (11) about 4 decades ago: “The develop-ment of left ventricular failure because of hyperten-sion determines a decrease of the previously raised BPto normal levels and, since the failure usually persists,the BP remains normal (11). If the patient recoversfromHF, then the BP rises and the diagnosis is likely tobe ‘hypertension.’ In other words, the “diagnosis”varies between dilated cardiomyopathy andhypertension according to left ventricular functionand only if a patient with dilated cardiomyopathy,HF actually recovers and develops high BP can thecausal or conditioning role of high BP be proved.”

Weevaluated this hypothesis in ameta-analysis andwere able to document that in patients with HF whounderwent cardiac resynchronization therapy (CRT)an increase in BP occurred. (12). CRT improves cardiacfunction by reverting asynchronous mechanicalevents, especially in patients with a wide QRS complexor with echocardiographic dyssynchrony. In analyzing18 studies we showed that CRT resulted in an increasein SBP by about 4 mm Hg, no change in diastolic bloodpressure and an increase in pulse pressure comparedwith baseline or medical therapy. In a recent study byTanaka et al. (13), an increase in SBP after CRT wasassociatedwith a decrease in the combined endpoint ofHF hospitalization and all-cause mortality.

FIGURE 1 Staging of Hypertensive Heart Disease

LV ¼ left ventricular.

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BP IN HF PATIENTS

Although hypertension is well known to trigger inci-dent HF, higher SBP in patients with established HFseems to paradoxically have a protective effect onsurvival. Numerous studies have shown that in pop-ulations with HF, high SBP is associated with im-proved, not adverse, outcomes (14–20) and this holdstrue for both acute (14–17) and chronic (18,19) HF. Aretrospective study examining 2,289 patients from theCOPERNICUS (Carvedilol Prospective RandomizedCumulative Survival) trial by Rouleau et al. (21) foundthat the lower the pretreatment SBP of patients in thecohort is, the higher the risk is of amajor clinical event.For each 10-mm Hg decrease in the pretreatment SBP,there was an 18% increase in the risk of death, 11%increase in the combined risk of death or hospitaliza-tion for HF, and 9% increase in the combined risk ofdeath or hospitalization for any reason.

The increase in central BP occurring with beta-blockade may be an additional reason for the benefi-cial effect of this drug class in HF. McAlister et al. (22)reported that the magnitude of heart rate reduction(which is indirectly proportional to the increase incentral pressure) is associated with the survival

benefit of beta-blockers in HF. The same phenome-non may be responsible for the benefits of heart ratelowering with ivabradine in patients with HF in theSHIFT (Systolic Heart failure treatment with the lfinhibitor ivabradine) trial (23). As discussed, in manypatients with HF, SBP is low, often critically so. In thissituation, an increase in central pressure secondary toheart rate lowering as has been documented withivabradine (24) may turn out to be beneficial. Thedecrease in cardiac workload with ivabradine is likelyto override a potentially detrimental effect, if any, ofa higher central systolic pressure. In contrast tohypertension, where heart rate lowering has beendocumented to progressively increase cardiovascularmortality, in HF there is an inverse correlationbetween resting heart rate and outcome (22,25).

CARDIORENAL SYNDROME

Both the heart and the kidney are target organs inhypertension and their function and structurebecomes progressively impaired with longstandinghypertensive cardiovascular disease. Not surpris-ingly, therefore, HF and renal failure commonly occurin the same patient as a sequence of hypertension.

FIGURE 2 Pickering Syndrome

Three main pathophysiological mechanisms contribute to the development of flash pulmonary edema: 1) defective pressure natriuresis with

sodium and fluid retention; 2) increased left ventricular end-diastolic pressure (LVEDP) associated with left ventricular hypertrophy and

stiffening; and 3) failure of the pulmonary capillary blood–gas barrier. BP ¼ blood pressure; HFpEF ¼ heart failure with preserved ejection

fraction; HFrEF ¼ heart failure with reduced ejection fraction; RAS ¼ renal artery stenosis.

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Cardiorenal interactions occur in both directionsand by a variety of mechanisms (26). The differentinteractions that can take place between heart andkidney have been thoroughly classified by Roncoet al. (27). In HF the most common types of car-diorenal syndrome (CRS) are:

Ty

Ty

Ty

Ty

pe 1 (acute): Acute HF leading to acute kidneyinjury (renal failure)

pe 2 (chronic): Chronic HF leading to progres-sive chronic kidney disease

pe 3: Acute, worsening of kidney functionleading to HF

pe 4: Progressive primary chronic kidneydisease leading to HF

From a clinical point of view, the occurrence ofrenal failure in HF, regardless of the exact CRS type,greatly complicates all therapeutic strategies. As

chronic kidney disease progresses, the prevalence ofHF increases and vice versa. The increase in comor-bidities, as well as on the need for incremental ther-apies, enhances the risk of hyperkalemia. From aclinical point of view, the presence of CRS drasticallylimits the therapeutic armamentarium in HF patients.Conceivably a treatment strategy with the newlyavailable Kþ binders in conjunction with a mineral-ocorticoid antagonist will help to reduce CV mortalityand morbidity in HF (28).

PICKERING SYNDROME

In 1988 Pickering et al. (29) reported a series of 11hypertensive patients with bilateral atheromatousrenal artery stenosis (ARAS) who presented with ahistory of multiple episodes of flash pulmonaryedema (FPE). The clinical entity of FPE and bilateralARAS, now known as Pickering syndrome (30), has

CENTRAL ILLUSTRATION Suggested Empirical Antihypertensive Strategy in HF Patients WithPersisting Hypertension

Messerli, F.H. et al. J Am Coll Cardiol HF. 2017;5(8):543–51.

ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; Ca ¼ calcium; HF ¼ heart failure; HFpEF ¼ heart failure

with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; LV ¼ left ventricular; LVEF ¼ left ventricular ejection

fraction; LVH ¼ left ventricular hypertrophy; SGLT2 ¼ sodium-glucose co-transporter 2 inhibitor.

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to be classified as CRS type 3. Patients with Pickeringsyndrome most commonly present with severelyimpaired LV filling and LV hypertrophy but mayhave normal or only mildly impaired LV systolicfunction. This, together with defective natriuresissecondary to bilateral ARAS, is the main pathoge-netic mechanism leading to FPE (Figure 2). The factthat flooding of the alveolar space can occur withinminutes resulting in an acute life-threateningemergency is what distinguishes FPE from otherforms of decompensated HF (31). Regardless of itsetiology, an acute increase of the LV end-diastolicpressure is the common denominator for the devel-opment of FPE (Figure 2). The presence of recurrent

FPE, lack of typical angina, increased BP, andelevated creatinine should raise the suspicion ofbilateral ARAS and hence Pickering syndrome as apossible etiology for FPE. In the series described byPickering et al., FPE occurred on average 2.3 timesbefore the diagnosis of ARAS was made, and, in ourstudy (21), three-quarters of all patients had morethan 1 episode of FPE. Classically, these patientshave some degree of renal failure and present withsudden onset of severe unprovoked dyspnea (“flash”pulmonary edema). The frequent nocturnal appear-ance of FPE may be related to reverse nocturnal BPdipping, a phenomenon that has been well docu-mented in patients with ARAS.

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Acute management of FPE is aimed at maintainingadequate oxygenation, diuresis, decrease of pulmo-nary capillary pressure, and treatment of underlyingcause. However, aggressive treatment of FPE inpatients with bilateral ARAS usually will cause afurther decrease of glomerular filtration rate andhyperkalemia may ensue. Renal revascularization isthe treatment of choice once the patient isstable and FPE has been resolved. The AmericanHeart Association/American College of Cardiologyguidelines endorse revascularization as a class 1recommendation for patients with hemodynamicsignificant ARAS and recurrent unexplained conges-tive HF or pulmonary edema (32). In our analysis, 92%of all patients had no further FPE after revasculari-zation (30). Patients with recurrent FPE after renalartery stenting should have repeat Doppler ultra-sound of the kidneys to rule out recurrent ARAS dueto restenosis.

ANTIHYPERTENSIVE THERAPY

FOR HF PREVENTION

By definition, all antihypertensive drugs lower BP.However, scrutinizing the literature reveals thatnot all antihypertensive drugs are created equal intheir propensity to prevent HF. b-Blockers remain acornerstone in the treatment of HF and recent reviewconcluded that “irrespective of age or sex, patientswith HFrEF in sinus rhythm should receive beta-blockers to reduce the risk of death and admissionto hospital” (33). Most disappointing it is, therefore,that b-blockers have no better preventive effect on HFthan do other antihypertensives. Among the 12 ran-domized controlled trials we analyzed, evaluating112,177 patients with hypertension, beta-blockersreduced BP by 12.6/6.1 mm Hg when compared withplacebo, resulting in a 23% (trend) reduction in HFrisk (p ¼ 0.055). (34) Compared with other antihy-pertensives, beta-blockers conferred similar but noincremental benefit for the outcomes of all-causemortality, cardiovascular mortality, and myocardialinfarction, but increased stroke risk by 19% in theelderly. Given this increased risk of stroke, beta-blockers should not be considered as first-lineagents for prevention of HF.

In a Cochrane meta-analysis, calcium-channelblockers (CCBs) increased the risk of HF events(risk ratio [RR]: 1.37; 95% confidence interval [CI]:1.25 to 1.51) as compared with diuretics. AlthoughCCBs reduced stroke as compared with ACE inhibitorsand reduced stroke and myocardial infarction ascompared with ARBs, CCBs also increased HF events

as compared with ACE inhibitors (RR: 1.16; 95% CI:1.06 to 1.27) and ARBs (RR: 1.20; 95% CI: 1.06 to1.36) (35). Stroke remains the most devastatingcomplication of hypertension, but prima vista CCBsare probably not the antihypertensive drug class ofchoice for the prevention of HF.

However, a recent meta-analysis concluded thatBP lowering by calcium antagonists is as efficaciousas BP lowering by other antihypertensive drugs inpreventing new onset HF (36). Thomopoulos et al. (36)reassessed the previously reported inferiority of CCBsin preventing HF and documented that the inferiorityof CCBs may depend on, at least to a large extent, anunequal use of accompanying drugs. The moreaggressive use of drugs known to reduce HF symp-toms (diuretics, b-blockers, and renin-angiotensinsystem blockers) in the control arms might havemasked onset of HF symptoms to a greater extent,thereby creating a bias against CCBs.

In the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial)study, the alpha-blocker doxazosin arm, comparedwith the chlorthalidone arm, conferred a higher riskof stroke and combined cardiovascular disease.Importantly, HF risk was doubled with doxazosin(4-year rates, 8.13% vs. 4.45%; RR: 2.04; 95% CI: 1.79to 2.32; p < 0.001) (34). This would indicate that forthe treatment of hypertension alpha-blockers shouldbe avoided in patients at risk for or with HF. Althoughthe data in aggregate are less convincing for alpha-blockers than for CCBs, specifically amlodipine, avery similar point as was made previously for CCBs(35) could be made for alpha-blockers. In ASCOT(Anglo-Scandinavian Cardiac Outcomes Trial), dox-azosin gastrointestinal therapeutic system given as athird-line add-on drug did not increase the risk of HFand was well tolerated (35).

Blockers of the renin-angiotensin system are effi-cacious drugs to treat hypertension and to preventHF. Contrary to the common clinical notion and tosome guidelines, no meaningful difference inefficacy has been documented between ACEinhibitors and ARBs (37,38). Of note, the first-in-classangiotensin II receptor neprilysin inhibitor valsartan/sacubitril not only is a novel drug for the treatmentof HF, but also is likely to become a useful antihy-pertensive drug. Recent data have indicated that itmay have a preferential effect on systolic pressure(39). A meta-analysis has shown better BP loweringwith valsartan/sacubitril than with ARBs. In thePARADIGM (Prospective Comparison of ARNI withACEI to Determine Impact on Global Mortality andMorbidity in Heart Failure) trial, valsartan/sacubitril

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showed a striking reduction in cardiovascular mor-tality and morbidity in patients with HFrEF (40). Ofnote, the long-term use of neprilysin inhibitors maycompromise beta-amyloid peptide degradation inthe brain, thereby possibly accelerating progressionof Alzheimer’s disease in patients at risk. Thus, itremains to be seen whether the risk–benefit ratio ofvalsartan/sacubitril confers incremental long-termprognostic benefits in patients with hypertension.

Finally, the thiazide-like diuretics chlorthalidoneand indapamide are outstanding agents when used asantihypertensive drugs to prevent HF. In the SHEPtrial (41) as well as in the HYVET (Hypertension in theVery Elderly Trial) trial (42) there was a highly sig-nificant reduction of HF with active therapy againstplacebo, amounting to an RR of 0.51 (95% CI: 0.37 to0.71) for chlorthalidone and 0.36 (95% CI: 0.22 to 0.58)for indapamide (p < 0.001 for both). The HF preven-tive efficacy of diuretics as a group in 10 randomizedcontrolled trials was clearly superior to the one of allother antihypertensives (RR: 0.84; 95% CI: 0.73 to0.98) (36). Of note, no outcome data are available forhydrochlorothiazide, for neither HF nor any othercardiovascular endpoint. In contrast to chlorthalidoneand indapamide, hydrochlorothiazide should beavoided in hypertensive patients at risk for HF.

In conclusion, most antihypertensive drug classeswhen used as initial therapy decelerate the transitionfrom hypertension to HF, although not all of them arecreated equal in this regard. Low-dose, once-dailyhydrochlorothiazide should be avoided, but thethiazide-like diuretics chlorthalidone and indapamide

seem to have an edge over other antihypertensivedrugs in preventing HF.

ANTIHYPERTENSIVE THERAPY IN HF

PATIENTS WITH PERSISTING HYPERTENSION

In most HF patients, too low a BP is a more commonclinical problem than is hypertension. However, somepatients with HFpEF and a few with HFrEF presentwith hypertension. Because no outcome data areavailable, our treatment recommendations are purelyempirical, based on clinical and pathophysiologicconsiderations (Central Illustration). Also, our recom-mendations of antihypertensive therapy are based onthe assumption that all HF patients are on baselinetriple therapy consisting of an ACE inhibitor or anARB, plus a b-blocker and a loop diuretic, and despitethis still exhibit residual hypertension. The proposedantihypertensive strategy is geared at improvingdiastolic and microvascular dysfunction in HFpEFand at improving or at least preserving systolicfunction in HFrEF. As a first step we suggest to in-crease afterload reduction by switching to valsartan/sacubitril (38) and to a vasodilating b-blocker suchas carvedilol or nebivolol. Clearly a statin should bepart of the therapeutic strategy in all patients withHFpEF to reduce microvascular dysfunction.

ADDRESS FOR CORRESPONDENCE: Dr. Franz H.Messerli, Department of Cardiology and Clinical Research,University Hospital, Bern, Freiburgstrasse, CH-3010 Bern,Switzerland. E-mail: messerli.f@gmail.com.

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KEY WORDS antihypertensive therapy,cardiorenal syndrome, HFpEF, hypertensiveheart disease, left ventricular hypertrophy,Pickering syndrome

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