Clin Chest Med 28 (2007) 91–115

Standard Therapies for PulmonaryArterial Hypertension

Shoaib Alam, MDa,*, Harold I. Palevsky, MDb,c,d

aDivision of Pulmonary, Allergy and Critical Care Medicine, Penn State University-Hershey Medical Center,

500 University Drive, Hershey, PA 17033, USAbUniversity of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA

cPulmonary, Allergy and Critical Care, Penn Presbyterian Medical Center, 51 N. 39th Street,

Philadelphia, PA 19104, USAdPulmonary Vascular Disease Program, Penn Presbyterian Medical Center, 51 N. 39th Street,

Philadelphia, PA 19104, USA

Pulmonary arterial hypertension (PAH) wasfirst described in 1891 in a case report byRomberg [1]. The term ‘‘primary pulmonary hy-

pertension’’ (PPH) was first used in 1951 whenDresdale and colleagues [2] reported clinical fea-tures and hemodynamics of 39 patients. Until

approximately two decades ago, before the de-velopment of specific PAH therapies, such asprostacyclin analogs, endothelial receptor antag-onists, and phosphodiestrase-5 inhibitors, PAH

(especially idiopathic [IPAH] or PPH form ofPAH) was considered a disease that was univer-sally fatal with a median survival of 2.8 years

[3]. An explosion of research and drug develop-ment has resulted in the development of severalspecific PAH therapies (see other articles else-

where in this issue) [4–21]. Therapies such as ox-ygen supplementation, calcium channel blockers(CCBs), anticoagulation, digoxin, and diuretics

have been in use since long before the develop-ment of the newer specific PAH agents. Thesetherapies have been referred to as ‘‘standardPAH therapies’’ or ‘‘conventional PAH thera-

pies’’ [22]. The concept of these standard thera-pies originated from the experience with otherpulmonary and cardiac diseases with similardbut not identicaldmanifestations in terms of symp-toms (eg, edema in congestive left heart failure and

* Corresponding author.

E-mail addresses: shoaibalam@yahoo.com;

salam1@psu.edu (S. Alam).

0272-5231/07/$ - see front matter � 2007 Elsevier Inc. All r

doi:10.1016/j.ccm.2006.12.003

use of diuretics) or physiologic observations (eg,hypoxemia in emphysema and use of oxygen sup-plementation therapy, low cardiac output in left

ventricular [LV] systolic dysfunction and use of di-goxin, high blood pressure in essential systemic hy-pertension and use of vasodilators, prothrombotic

tendency in venous thromboembolism and useof anticoagulation). These practices were subse-quently adopted in the treatment of PAH and rightheart dysfunction and failure. None of these thera-

pies is supported by well-designed placebo-con-trolled trials. Some of these practices are based onmarked symptomatic relief or improvement with

short-termuse (eg, diuretics for edema) or by obser-vations based on acute testing in the laboratory set-ting (eg, improvement in cardiac output by single

administration of digoxin) [23] or from autopsyfindings [24–26] (eg, in situ microthrombi in lungsof patients who have PAH and use anticoagula-

tion). Therapies such as anticoagulation havebeen supported by a few retrospective studies[27,28] and an uncontrolled, single-center prospec-tive study [29], especially in IPAH [30]. This raises

the ethical question of the appropriateness of per-forming a placebo-controlled trial in these patients.On the other hand, the short-term benefits from di-

uretics are so obvious that it virtually obviates theneed for a clinical trial to validate such benefit.For these reasons it seems unlikely that any

large, prospective, clinical trials will examine therole of the standard therapies used in PAH in thenear future. Such trials are needed, however.

ights reserved.

chestmed.theclinics.com

92 ALAM & PALEVSKY

Especially lacking are data about use of standardtherapies in PAH other than IPAH (associated[APAH]). It may be possible that in specific popu-

lations, these therapies may not be helpful,that they may be less helpful than they arecurrently considered, or that they may be evenharmful.

In a prospective, controlled study of patientswho had PAH and Eisenmenger syndrome, theuse of oxygen supplementation in hypoxemic

patients was not associated with any improve-ment in hematologic variables, quality of life, orsurvival [31]. A recent retrospective chart review

of French patients who had IPAH showed thatonly 6.8% of all patients who had IPAH couldbe maintained on CCB therapy alone withoutany need for augmentation of therapy by

a newer agent [32]. This is an example in whichretrospective [33] and noncontrolled prospective[29,34] data led to enthusiasm, first about the

use of acute vasoreactivity testing for assessingprognosis in PPH and second about the exces-sive use of CCBs in patients who have PAH.

It should be noted that the initial studies[29,34], which reported that the ‘‘responders’’had an excellent (94%) 5-year survival on

CCBs, had mean fall in mean pulmonary arterypressure (mPAP) of 39% to 48% and mean fallin pulmonary vascular resistance (PVR) of 53%to 60%. The acceptance of relatively less strin-

gent criteria for favorable acute vasoreactivityresponse [35–37] was at least partly caused bythe fact that at that time the only alternative

to CCB therapy was continuous intravenousprostacyclin therapy. Because currently severaloral and inhaled therapies are available and it

is known that as many as 46% of ‘‘acuteresponders’’ eventually will fail, CCB monother-apy [32], the need for and emphasis on perform-ing acute vasoreactivity testing, and the use of

CCBs as primary therapy for IPAH has changed[32]. Reliance on CCBs in such patients and notusing specific PAH therapies may or may not be

in patients’ best interest.This article reviews current recommendations

and widely accepted practices regarding the use

of standard therapies in PAH and presents theevidence available to support these practices.The primary purpose of this article is to pro-

vide clinicians with relevant information to beable to make informed therapeutic decisions inclinical situations in which data regardingstandard therapies are lacking, relative contra-

indications to these therapies exist, or the

therapies are poorly tolerated or adverse eventsoccur.

Oxygen therapy

The value of long-term oxygen supplementa-tion therapy in patients with PAH has not beenevaluated by well-designed clinical trials. Recom-mendations and guidelines for oxygen therapy in

patients who have PAH have been extrapolatedfrom the clinical data available for chronic ob-structive pulmonary disease (COPD). Pathophy-

siologically, hypoxemia is a potent stimulus forpulmonary vasoconstriction [38]. In COPD pa-tients who have hypoxemia, two well-designed,

prospective, randomized, non–placebo-controlledtrials [39,40] have shown that there is marked im-provement in long-term survival with the use ofsupplemental oxygen (Table 1) [31,39,40].

One trial [40] studied87patientswhohadCOPDand a history of right heart failure (RHF) alongwith arterial oxygen partial pressure !60 mm Hg.

Patients were randomly assigned to receive 15 h/dof oxygen supplementation therapy or no therapy.Five-year mortality rate in the oxygen treatment

group was 46%versus 67% in control group (num-ber needed to treat to save one life in approximatelyfive). The study also showed an increase in PVR in

the control group over the study period but noincrease in PVR in the oxygen therapy group. Thestudy was not powered to evaluate this parameter,however.

The other prospective, randomized, controlledstudy of 203 patients who had chronic hypoxemicCOPD showed that in patients who were hypox-

emic at rest during the daytime, the use ofnocturnal oxygen supplementation (12 h/d) wasassociated with a higher 3-year mortality rate

(42% versus 22%) when compared with the groupthat used continuous (at least 19 h/d) supplemen-tal oxygen [39]. The number needed to treat to

save one life was approximately five. The survivaladvantage was more pronounced in patients withless severe pulmonary hypertension at baseline(mean pulmonary arterial pressure !27 mm

Hg). Continuous oxygen supplementation therapyimproved long-term survival in patients who hadCOPD with significant hypoxemia (PaO2 !55

mm Hg at rest) even if there was no significant im-provement in pulmonary hemodynamics withacute oxygen supplementation. Patients with low

baseline PVR had an improved mortality on con-tinuous oxygen supplementation therapy, but thepatient with high baseline PVR did not experience

Table 1

Comments

herapy

eater than

01). 1-y and

and 41%,

l therapy

2%,

us therapy

No placebo control and no blinding

was used

NOTE: the trial involved COPD pa-

tients and not WHO I PAH

patients; hence the results should

be extrapolated with caution

The survival benefit was also present

in patients with low mean pulmo-

nary artery pressure and PVR and

with relatively preserved exercise

capacity

Survival advantage was pronounced in

hypercapnic patients but was also

present with relatively poor lung

function, low mean nocturnal

oxygen saturation

oup was

ntrol

xygen did

ys of

No placebo control and no blinding

was used

NOTE: the trial involved COPD

patients and not WHO I PAH

patients; hence the results should

be extrapolated with caution

did not

riables, 6-

uality of

llow-up

It is not known whether continuous

oxygen therapy will be helpful in

this patient population

Two patients died in oxygen therapy

groups and three patients died in

control group; probably the

numbers were too small to reliably

conclude ‘‘no difference’’ between

the two groups

This study clearly highlights that

similar interventions may have

entirely different impact on different

disease processes

93

STANDARD

THERAPIE

SFOR

PAH

Clinical studies: oxygen therapy

Study [reference] (N) Design, method Follow-up duration, site Study findings

Nocturnal Oxygen

Therapy Trial

Group,

1980 [39] (203)

Prospective, randomized, non–

placebo-controlled trial,

multicenter

Patients with chronic, hypoxic COPD

Patients received either continuous

oxygen therapy or 12-h oxygen

therapy

At least 12 months, at

six centers in United States

Overall mortality in 12-h t

group was 1.94 times gr

continuous group (P ¼ .

2-y mortality was 21%

respectively, in nocturna

group versus 12% and 2

respectively, in continuo

group

Medical Research

Council Working

Party, 1981

[40] (87)

Prospective, randomized, non–

placebo-controlled trial, multicenter

Patients with chronic, hypoxic cor

pulmonale secondary to COPD

42 patients received oxygen at 2 L/min

at least 15 h/d and 45 control

patients received no oxygen

Five years, at three

centers in U.K.

5-y mortality in treated gr

significantly less than co

(45% versus 67%)

Survival advantage from o

not emerge until 500 da

therapy

Sandoval et al,

2001 [31] (23)

Prospective, randomized, non–

placebo-controlled trial, single center

Patients with congenital heart disease

and Eisenmenger’s syndrome. 12

randomly assigned patients received

nocturnal oxygen for at least 8 h at

flow rate (mostly 2–3 L/min) that

increased the oxyhemoglobin

saturation from 79 � 6.5% to

88 � 6.0%

Two years, at a center

in Mexico

Nocturnal oxygen therapy

improve hematologic va

minute walk distance, q

life, or survival at 2-y fo

N ¼ Number of subjects.

94 ALAM & PALEVSKY

a survival benefit. Patients who showed a largedecrease in PVR on repeat right heart catheteri-zation after 6 months of continuous oxygen

therapy had greater mortality compared with pa-tients with smaller decrease in PVR [39]. This find-ing suggests that mortality benefit in hypoxemicpatients who have COPD and are on continuous

long-term oxygen therapy is probably not derivedfrom any reduction in PVR. This observation isimportant from the standpoint of oxygen therapy

in patients who have PAH.Because of the substantial survival (and hemo-

dynamic) benefit observed in COPD patients who

have hypoxemia, the oxygen supplementationtherapy is widely used in PAH patients whohave hypoxemia. The principles and criteria usedfor oxygen therapy in PAH are derived from the

studies and practice guidelines for treatment ofhypoxemic patients who have COPD [41].

Many patients who have PAH have hypoxemia

at rest, with exertion, or during sleep. Hypoxemiain PAH is thought to be caused by low mixed-venous oxygen tension secondary to low cardiac

output, altered diffusion capacity, and ventilation-perfusion mismatch. Some patients who have PAHpresent with relatively rapid worsening of hypox-

emia secondary to opening of a patent foramenovale, which results in right-to-left shunt. In suchpatients, hypoxemia is relatively refractory tooxygen supplementation. In most other patients,

however, with the exception of patients withadvanced disease, the hypoxemia at rest and atnight can be corrected by oxygen supplementation

at 2 to 6 L/min via nasal cannula, althoughincreased oxygen supplementation is frequentlyrequired during activity or exertion.

Most current guidelines [29,32–34] from Amer-ican or European professional societies recom-mend that all patients with PAH whose PaO2 isconsistently !55 mmHg or in whom oxyhemoglo-

bin saturation is %88% at rest, during sleep, orwith ambulation should be prescribed sufficientsupplemental oxygen therapy to keep the pulse

oximetry oxyhemoglobin saturation O90% at alltimes. In patients with laboratory or clinical find-ings that suggest chronic hypoxemia (eg, hemato-

crit O55%), clinical signs of RHF, or suggestionof RHF on EKG or echocardiography, long-termoxygen supplementation therapy should be initi-

ated at PaO2 !60 mmHg or oxyhemoglobin satu-ration of %89%. Such patients should be retestedfor oxygen requirement 3 months after the initia-tion of oxygen therapy. All patients with moderate

to severely decreased diffusion capacity (DLCO

!60% of predicted) at rest should be tested forpossibility of oxyhemoglobin desaturation with ac-tivity and while sleeping [42,43]. It should be noted

that all such recommendations are based on expertopinion in the absence of any direct evidence inIPAH or any form of APAH except pulmonary hy-pertension (PH) associated with COPD.

Many patients with congenital heart diseasehave hypoxemia secondary to right-to-left shunt.Such hypoxemia is relatively refractory to oxygen

supplementation therapy. The use of oxygen sup-plementation therapy in patients who have con-genital heart disease and Eisenmenger syndrome

remains controversial. A study of 15 pediatricpatients with PAH associated with congenitalheart disease and hypoxemia initially reportedimproved mortality with oxygen supplementation

for a minimum of 12 h/d for 5 years [44]. A well-de-signed, prospective, randomized, controlled studyof 23 adult patients who had hypoxemia and Eisen-

menger syndrome showed that nocturnal oxygensupplementation had no effect on survival, qualityof life, hematocrit, or 6-minute walking distance

[31]. Some studies suggest that oxygen supplemen-tation in these patients may reduce need forphlebotomy and may reduce neurologic complica-

tions [35]. Nocturnal oxygen supplementation inchildren who have PAH associated with congenitalheart disease has been shown to decrease the rate ofprogression of polycythemia. Similarly in the PAH

pediatric population, oxygen therapy has beenshown to improve symptoms [44,45].

PaO2 during sleep is almost always lower than

PaO2 while awake [46], which is probably second-ary to sleep-induced hypoventilation and the resul-tant rise in PCO2. In normal individuals with

a normalwakePaO2, nocturnal oxyhemoglobin de-saturation is not seen because the oxyhemoglobindissociation curve is relatively flat for PaO2 above90 mm Hg. Patients who are hypoxemic at rest

while awake are always more hypoxemic duringsleep, however [47]. This reduction in arterial oxy-genation is even more pronounced during rapid

eye movement sleep. The long-term value of treat-ing nocturnal hypoxemia in patients who havePAH remains unclear, however. Screening with

nocturnal oximetry may be performed to evaluatepossibility of nocturnal hypoxemia when clinicallysuspected. Oxyhemoglobin saturation !90% for

less than 5% of the recording time may be consid-ered clinically insignificant regardless of the lowestrecorded oxyhemoglobin saturation value. Afterinitiation of oxygen supplementation, it is sug-

gested that a repeat nocturnal oximetry study be

95STANDARD THERAPIES FOR PAH

obtained to assess the adequacy of nocturnaloxygen supplementation therapy.

In most patients without significant right-to-left shunt, a nocturnal oxygen supplementation at

2 to 3 L/min above the resting oxygen requirementis sufficient to maintain adequate oxygenationduring sleep. The exception to this rule is presence

of obstructive sleep apnea (OSA), in which nasalcontinuous positive airway pressure (CPAP) (orBiPAP) therapy is needed to correct the sleep-

disordered breathing and hypoxemia. An over-night polysomnogram should be ordered forpatients in whom OSA is suspected because of

history of snoring, excessive daytime sleepiness, orwitnessed apneas. Routine ordering of polysom-nogram in all patients who have PAH is notindicated [48].

Prevalence of PH in OSA is much higher thanthe prevalence of IPAH in the general population;the reported prevalence of PH in OSA is 17% to

53% [48–60]. In contrast, the estimated incidenceof IPAH in the general population is 1 to 2 newcases per million [61], which suggests a prevalence

of !10 to 20 per million. Most of the studies [48–60] that estimated prevalence of PH in OSA usedright heart catheterization for defining PAH.

Data are difficult to interpret, however, becausemany of these studies defined PH as mPAP R20mm Hg (less than the standard used to definePAH) or used estimated pressures by echocardio-

gram. Generally PH associated with OSA is mildin the absence of obesity-hypoventilation syn-drome [47–59]. Any moderate or severe PH

should not be attributed to OSA alone, no matterhow severe the OSA. Modest improvement in PApressures is expected from the treatment of OSA;

the expected median decrease in pulmonary arterypressure is 3 to 6 mm Hg and expected mediandecrease in PVR is approximately 0.5 wood units[59,62,63]. Patients who have OSA and PH with

hypoxemia who are treated with CPAP and oxy-gen supplementation have a more pronounceddecrease in mPAP and PVR than patients who

are treated with oxygen therapy alone. Resolutionof PH is not an expected outcome of even themost successful therapy by CPAP, regardless of

the severity of OSA and the duration of theCPAP therapy [59,62,63].

Obesity-hypoventilation syndrome (usually as-

sociated with body mass index O34 and alwaysassociated with the presence of daytime hyper-capnia, ie, PCO2 of R45 mm Hg) can be associ-ated with severe PAH and RHF, regardless of

presence or absence of concurrent OSA [64].

Oxygen supplementation or CPAP therapy orboth combined are not adequate treatments fornocturnal hypoxemia in such patients; noninva-sive positive pressure ventilation or bilevel posi-

tive pressure ventilation should be used. Inpatients who cannot tolerate this therapy (eg, be-cause of claustrophobia), tracheostomy should be

offered along with chronic outpatient mechanicalventilation. Near complete reversal of hypercap-nia and signs of RHF within a few months with

invasive or noninvasive mechanical ventilationtherapy usually are seen in patients who do nothave concurrent factors contributing to the devel-

opment of PAH [65]. Weight loss after gastric sur-gery for morbid obesity also has been shown tosubstantially decrease the PCO2 (mean, 52 mmHg to 42 mm Hg) and mPAP (mean, 36 mm Hg

to 23 mm Hg) at right heart catheterization [66].In patients who have PH and a body mass indexO34, an arterial blood gas analysis obtained on

room air, should be performed to rule out possibil-ity of obesity-hypoventilation syndrome (OHS)because the management principles of OHS associ-

ated PAH are different than those of OSA [65,66].There is reluctance on the part of some physi-

cians and many patients to consider oxygen

supplementation as part of therapy. Oxygensupplementation is a major lifestyle change forpatients (with the exception nocturnal oxygensupplementation therapy alone). Factors such as

cost, the type of equipment required, and theinconvenience ofmany ambulatory oxygen systemsimpact on patients’ acceptance and use of pre-

scribed supplemental oxygen. In clinical practicemost patients agree to the use of oxygen if pre-scribed by physician but do not like the oxygen

tubing they need to wear in public. This has animpact on their perceptions of themselves andothers’ perceptions of them. Falls associated withlong cords and tubing attached to oxygen concen-

trators and other oxygen delivery systems canoccur.

Diuretics

The long-term role of diuretics in RHF andPAH has not been systematically studied. The useof diuretics in patients who have PAH with

peripheral edema secondary to RHF is wide-spread and universally accepted. Almost allPAH patients with peripheral edema secondary

to RHF are treated with diuretics, and the effectof the diuretics on edema is usually obvious. Mostpatients with edema report some improvement

96 ALAM & PALEVSKY

after ‘‘effective diuresis’’ as assessed by change inweight or pedal edema over relatively shortperiods of time. For many patients, maximal

effects are only obtained when salt and fluidintake restrictions are used with diuresis. Whetherdiuretics alter mortality or morbidity in patientswho have PAH with RHF is not known, however.

Diuretics also can decrease the sensation ofdyspnea in patients with enlarged right heartchambers compromising left heart function (see

later discussion).The effect of most diuretics (eg, furosemide) on

mortality or morbidity either in left or right heart

failure has not been evaluated by long-term trials.Spironolactone, an aldosterone antagonist used asa potassium-sparing diuretic, decreased mortalityin a long-term prospective, randomized, placebo-

controlled trial of patients with recent hospitali-zation for severe left heart failure with NYHA IIIor IV symptoms [67]. In this study, a relatively low

dose of spironolactone (12.5 mg/d taken orally)was used as an add-on therapy to angiotensin-converting enzyme inhibitor therapy. Two-year

mortality rate in the treatment group was 35%compared with 46% in controls, indicating 24%relative risk reduction (number needed to treat

to save one life in approximately nine). The studyalso showed a 35% decrease in hospitalizationssecondary to worsening of heart failure and im-provement in functional class in treated patients.

No studies have evaluated the long-term role ofaldosterone antagonists in patients who havePAH and RHF. Secondary to convincing data re-

garding left heart failure, however, spironolactoneis widely used in patients who have PAH andRHF as an adjunct to loop diuretics. Long-term

value of spironolactone in such patients remainsunknown. It should be noted that many interven-tions known to have a beneficial effect in LV fail-ure (eg, angiotensin-converting enzyme inhibitors

and beta adrenergic antagonists) have not beenproven to be beneficial in patients who havePAH and RHF. Spironolactone should not be

used in patients with serum creatinine O2.5 mg/dLor potassium O5.0 mEq/L or in patients withhistory of severe refractory hyperkalemia. Extreme

caution should be observed in patients who haveimpaired renal function or diabetes, in elderlypersons, and in patients with concurrent use of

angiotensin-converting enzyme inhibitors or non-steroidal anti-inflammatory agents [68].

Amiloride (a potassium-sparing diuretic) ana-logs have been shown to inhibit development of

hypoxia-induced pulmonary hypertension in

animal models [69]. The proposed mechanism isinhibition of sodium-proton (Naþ/Hþ) exchangeto prevent intracellular alkalinization, which seems

to play a permissive role in pulmonary arterysmooth muscle cell proliferation in the process ofvascular remodeling [24]. There are no clinicalstudies in patients who have PAH to speculate the

clinical significance of these observations.In most recent trials of pharmacologic therapy

for PAH [4–21], diuretics were used as adjunct

therapy in a large proportion of patients, but theeffect of diuretics was not tested as an end pointin any of these trials. In severe RHF, large doses

of diuretics may be required for effective diuresis.Some patients may require doses as high as furose-mide, 600 mg/d, or bumetanide, 10 mg/d, or theaddition of metolazone (up to 20 mg/d). Edema

in many patients with severe RHF and impairedrenal function may be disabling and can be refrac-tory to even such high doses of diuretics (Box 1).

Right ventricular (RV) performance is preloaddependant. Because of ventricular interdepen-dence (ie, shared pericardium and septum), how-

ever, extreme RV dilatation may compromise LVfilling in part by displacing the interventricularseptum into the LV, which results in LV diastolic

dysfunction and a decrease in cardiac output [70–72]. Patients who have PAH are likely to developinterstitial edema at relatively lower pulmonarycapillary wedge pressures because the effective

hydrostatic pressure to favor interstitial edemaformation is equal to pulmonary capillary wedgepressure plus 40% of the gradient between

mPAP and pulmonary capillary wedge pressure(Gaar’s equation). Relatively minor fluctuationsin fluid status may result in significant change in

cardiac output or gas exchange, resulting in arte-rial hypoxemia. Caution should be observedwhen adjusting diuretic dose. There is no evidenceor scientific rationale to urgently diurese patients

or remove large volumes of fluid over a shortperiod of time, except when there is cardiogenicpulmonary edema or acute worsening of arterial

hypoxemia. ‘‘Optimal fluid status’’ in patientswho have PAH and RHF is often a relatively nar-row window in which patient’s cardiac output is

maintained, arterial hypoxemia is minimized,and signs of tissue perfusion (as assessed by renalfunction, presence or absence of peripheral cyano-

sis, or altered mentation) are optimal.Severe passive hepatic congestion and bowel

wall edema and ischemia may be present whenpatients who have severe RHF and reduced

cardiac output present with significantly deranged

97STANDARD THERAPIES FOR PAH

Box 1. Management optionsfor refractory edema in pulmonaryarterial hypertension and severe chronicright heart failure

History and evaluation� Carefully review compliance with salt

and water intake restriction.� Consider concurrent medications

(eg, CCB, bosentan, sitaxsentan, orprostacyclin analogs) and temporalrelation to the worsening of edema.� Review possibility of worsening of

underlying disease by otherparameters (eg, 6-minute walkingdistance, oxygen requirement, RVhypertrophy on echocardiography).� Reassess renal function.� Consider discontinuing all

nonsteroidal anti-inflammatory drugs.

Options� Increase the dose of current

loop diuretic (may use up tofurosemide, 600 mg/d, or bumetanide,10 mg/d).� Add a diuretic from another class

(metolazone, 2.5–5 mg twice daily, orspironolactone, 12.5–50 mg twicedaily). Do not use spironolactone ifserum creatinine is above 2.5 mg/dL orabove 1.6 in patients older than70 years. Do not use in patients whohave diabetes or potassium above4.5 or history of severe hyperkalemia.� Change current loop diuretic to

another loop diuretic.� Consider hospitalization and

intravenous diuretics.� Consider hospitalization and

ionotropic support by very low dose(2–3 ng/kg/min; avoid higher doses)IV dopamine or dobutamine.� Consider atrial septostomy (if

appropriate for patient).� Consider lung transplantation (if

appropriate for patient).� Consider right ventricular assist device

(if appropriate for patient).� Tolerate current level of edema.� Discuss end-of-life issues (if

appropriate for patient).

liver function tests or a sepsis-like picture second-ary to translocation of colonic micro-organisms asa consequence of bowel wall edema and bowelischemia. Patients may present with abdominal

pain, mild diffuse abdominal tenderness (withoutrebound or rigidity), and occult blood in thestools with or without gram-negative bacteremia.

This may be a terminal event in patients who havePAH and severe RHF. The appropriate therapymay include use of diuretics or IV fluids. Depend-

ing on the individual patient, low-dose dopamineor dobutamine (2–3 mg/kg/min) and inhaled NO(10–40 ppm) or inhaled prostacyclin (started at

50 ng/kg/min and titrated down to lowest effectivedose) IV antibiotics covering colonic flora (ie,covering gram-negative and anaerobic bacteria)should be considered. There are no published data

to define the optimal way to manage acutelydecompensated patients who have severe PAHand acute RHF.

Diuretic dosing should be revised if patientsdevelop orthostatic dizziness, which temporallycorrelates with decreased edema, decreased weight,

and recently increased diuretic dose. Charting ofdaily weights, use of written sliding scale fordiuretics, and potassium use, based on edema or

weight, may be useful strategies. Many patientswho have severe PAHandRHFhave relatively lowsystemic blood pressure. Diuretics should be usedwith caution in these patients. Concern over low

blood pressure and subsequent underdosing ofdiuretics actually may result in worsening of edemaor overall clinical worsening, however [68].

Potassium supplementation should be man-aged carefully, especially if there is worsening orfluctuation of renal function, addition or with-

drawal of potassium-sparing diuretics, or concur-rent use of digoxin. Arrhythmias, prolongedpalpitations, or syncopal episodes may be second-ary to PAH and RHF; however, in patients on

diuretics, electrolyte and digoxin level testingshould be considered.

Edema is a relatively common side effect of

many PAH therapies (eg, CCBs [2%–15%],bosentan [4%–8%], sitaxsentan [7%], and lesscommonly, prostacyclin). Adjusting the dose of

diuretics often can ameliorate such edema. Insome instances, however, this medication-relatededema is refractory to diuretics. Patients may

benefit from scheduled elevation of legs, com-pression stockings, or, if possible, switchingfrom the suspected causative agent to otheralternatives. In other instances in which the

PAH therapy is otherwise believed to be

98 ALAM & PALEVSKY

effective, patients are asked to tolerate increasedpedal edema.

Digoxin

Cardiac glycosides such as digoxin increase myo-cardial contractility by blocking sodium-potassiumadenosine triphosphatase pump (Naþ-Kþ ATPase)

[73], which is present in the cell membrane ofmyocardial cells. In patients who have PAHand RHF, a single intravenous administration

of digoxin has been shown to increase cardiac

output and decrease circulating norepinephrinelevels in a small, short-term, uncontrolled study(Table 2) [23]. This study included 17 patients

who received a single dose of 1 mg IV digoxinover a 30-minute infusion; hemodynamic mea-surements were made 2 hours after the infusionand were compared with baseline hemodynamic

values. A prospective, randomized, double-blind,placebo-controlled study [74] of 15 patients whohad COPD and RHF and no clinical LV failure

found that 8 weeks administration of digoxindid not improve RV ejection fraction in any

Table 2

Clinical studies: pulmonary arterial hypertension and digoxin

Study

[reference]

(N) Design method

Follow-up

duration,

site Study findings Comments

Mathur et al,

1981 [74]

(15)

Prospective, randomized,

placebo-controlled

trial, single center

Patients who have

RV failure secondary

to COPD and no

known LV failure

8 wk,

McMaster

University

in

Canada

At baseline, RV

ejection fraction was

reduced (on

equilibrium

radionuclide

angiography) in all

patients and reduced

LVEF was seen

in 4 patients

8 wk digoxin use, all

the abnormal LVEF

were normal;

however, Digoxin

increased RVEF

only in patients

who had

reduced LVEF

at baseline

It is not clear whether the

reduced LVEF at baseline

actually represents LV

disease or simply reflects

severely dilated RV causing

LV dysfunction or coexisting

LV disease; conversely,

normalization of LV systolic

function by 8-wk digoxin

therapy in all 4 patients

with low baseline LVEF is

unusual for LV systolic

dysfunction

NOTE: the trial involved

COPD patients with RV

failure and not WHO I PAH

patients; hence the results

should be extrapolated with

caution

Rich et al,

1998 [23]

(17)

Prospective, single-center

study; patients’ baseline

was used as control

Patients with PPH diagnosis

by NIH registry criteria

and normal LV function

on echocardiogram

Short-term

study

involving

hemodynamic

measurements

before and

after single

administration

of digoxin

1 mg IV over

30 min,

University of

Illinois

Single administration

of 1 mg IV digoxin

was associated with

significant increase

in cardiac out put

(3.49 � 1.2 to

3.81 � 1.2 L/min)

measured 2 hours

after the completion

on digoxin infusion

No placebo control was used

NOTE: the study was

short-term and no definitive

conclusion can be drawn

regarding effect on cardiac

output after long-term use

NOTE: the trials in LV systolic

dysfunction did not show

any prolongation of survival

with long-term digoxin use

(subgroup analysis, however,

did show reduced mortality

and hospitalizations in

patients with LVEF below

25%, NYHA class III or IV

functional class, or patients

with cardiomegaly on chest

radiograph)

N ¼ Number of subjects.

99STANDARD THERAPIES FOR PAH

patient who did not have reduced left ventricu-lar ejection fraction (LVEF) on baseline equilib-rium radionuclide angiography (see Table 2)[23,74]. The safety, efficacy, and impact on mor-

bidity or mortality with long-term use of digoxinin patients who have PAH and RVF are notknown. It should be noted that in patients

with systolic LV dysfunction and NYHA classII and III symptoms, treatment with digoxinfor 2 to 5 years did not have any impact on

mortality [75]; there was some beneficial effecton rate of congestive heart failure-relatedhospitalizations, however.

Currently, digoxin is used in patients whohave PAH and signs of RHF and in patientswho have atrial rhythm abnormalities (eg, multi-focal atrial tachycardia, atrial flutter, or atrial

fibrillation). Some experts advocate using digoxinwith calcium channel antagonists to counteractnegative ionotropic effects of CCBs. Because

most patients who have PAH and RHF are ondigoxin and diuretics, it is important to takeextreme caution to monitor digoxin levels and

promptly recognize toxicity, especially in associ-ation with electrolyte disturbances that resultfrom the use of diuretics. Paroxysmal atrial

tachycardia with variable atrioventricular blockand bidirectional tachycardia are well-knownarrhythmias associated with digoxin toxicity.The half-life of digoxin is prolonged with wors-

ening of renal function. Digoxin is renally clearedand is used in most US centers, whereas digitoxinis hepatically cleared and is mostly used in

European centers.There are no specific recommendations re-

garding how to monitor digoxin therapy in

patients who have PAH, so guidelines developedfor monitoring of digoxin therapy in patients withLV failure are relied upon [68]. Digoxin therapymay be started at 0.125 to 0.25 mg orally daily;

however, many centers only use low-dose (ie,0.125 mg/d) therapy. In patients with normalrenal function the digoxin levels may be first

checked after 1 week. In patients above age 70with impaired renal function or low body weight,a reduced starting dose [76] (0.125 mg every other

day) is more appropriate. When digoxin is usedfor positive ionotropic effect, it is generally recom-mended to keep the digoxin trough level between

0.5 and 1.0 ng/mL [68]. At a plasma concentrationabove 1.0 ng/mL, the risk-adjusted mortality in-creases, as shown by the Digitalis InvestigationGroup Trial [77]. In the absence of hypokalemia,

hypomagnesemia, or hypothyroidism, digitalis

toxicity is generally not seen below a plasma di-goxin concentration of 2.0 ng/mL (although di-goxin toxicity may rarely be seen at lowerconcentrations) [78,79]. Digoxin should not be

used in cases of suspected coronary ischemia orin patients with recent acute coronary syndromebecause of increased risk of death from arrhyth-

mia or myocardial infarction [68,75,80,81]. Con-current use of clarithromycin, amiodarone,itraconazole, cyclosporine, and many other drugs

can increase digoxin levels and increase the poten-tial for toxicity [82–84].

Anticoagulation

Currently no prospective, randomized, pla-cebo-controlled trials are available to provideevidence for or against the use of anticoagulationin patients who have PAH. Currently, it is a widely

accepted practice to use anticoagulation in pa-tients who have PAH (WHO group I [35]) unlessthere is a contraindication.

Patients who have significant PAH may havea sedentary lifestyle. Venous engorgement andstasis (as a result of elevated right atrial pressures)

and poor flow through pulmonary and systemiccirculations as a consequence of low cardiac outputplace them at increased risk for developing venous

thromboembolism. The pulmonary vascular bed isalready significantly compromised in patients whohave PAH by the time they become symptomaticand the diagnosis is made. As a consequence, even

a relatively minor pulmonary embolic event hasmore significant hemodynamic and gas exchangeconsequences and may be life threatening.

Substantial evidence from human studies ofbiochemical and serologic markers suggests pres-ence of a prothrombotic state in patients who

have PAH. Three key elements that influenceexistence of a prothrombotic state are endothelialfunction, platelet activation, and plasma proteins

related to coagulation and fibrinolysis. Certaincomponents of these three elements have beenshown to have aberrant behavior favoring a pro-thrombotic state in several human studies in-

volving patients with idiopathic and associatedforms of PAH (Table 4) [85–93]. The evidence ofthese prothrombotic abnormalities is more ro-

bust in IPAH and chronic thromboembolic pul-monary hypertension (CTE-PHT) than mostother forms of PAH. Some of these abnormali-

ties have been shown to reverse with specificPAH therapies, such as intravenous prostacyclin[94–97] or bosentan [98].

ents

ine was used if heart rate was O100/min,

zem was used if heart rate !100/min,

ing

20 mg or 60 mg, respectively. This was

wed by repeated doses every 1 h (all patients

PA catheter in place) until 50% fall in PVR,

fall in mPAP, or an untoward side effect

hypotension, dizziness, or worsening of

xemia])

erm dose of CCB: Up to 720 mg/d diltiazem

40 mg/d nifedipine

ient was treated with anticoagulants

ponders in this study had fall in PAP by 48%

in PVR by 60%, which is much more

ounced than most current criteria for

ing a positive acute vasoreactivity test

udy also involved use of warfarin in all

patients with nonuniform perfusion on V/Q

(55% of all)

f responders and 57% of nonresponders had

niform perfusion of V/Q scans

ponders in this study had fall in PAP by 39%

in PVR index by 53%, which is much

e pronounced than most current criteria

efining a positive acute vasoreactivity test

100

ALAM

&PALEVSKY

Table 3

Clinical studies: pulmonary arterial hypertension and calcium channel antagonists

Study

[reference]

(N) Design method

Follow-up

duration, site Study findings Comm

Rich et al,

1987

[34] (13)

Prospective, single center,

uncontrolled

PPH patients who were

‘‘responders’’ as defined by

patients who had a fall in

PAP and PVR by 20%

after acute CCB challenge

(8 out of 13 patients) and

were treated with high-dose

CCB in long-term

NOTE: acute vasoreactivity

testing with CCB has been

abandoned secondary to

the high frequency of

untoward events such as

profound hypotension.

Currently the testing is

performed with inhaled

nitric oxide, IV adenosine,

IV or inhaled prostacyclin

1 y, University

of Illinois

At 1 y, 5 patients returned for follow-up; 4 of

these 5 patients had sustained reduction in PVR

and PAP and regression of RV hypertrophy by

echocardiogram and electrocardiogram

NOTE: In the study once the effective dose was

determined, the drug was administered in

divided doses (every 4–8 h) to achieve total desired

daily dose.More frequent and small doses (every 4

h) were used in patients who did not tolerate

higher, less frequent dosing (every 8 h). Some

patients were started at low dose of CCB

(nifedipine, 20 mg, tid or diltiazem, 60 mg, tid) as

outpatients and the dose was slowly titrated to

desired dose (as determined at the time of acute

CCB testing) over 6 wk. Digoxin was also started

in these patients to counteract negative

ionotropic effects of CCB.

Nifedip

diltia

start

dose

follo

had

33%

[eg,

hypo

Long-t

or 2

No pat

The res

and

pron

defin

Rich et al,

1992

[29] (64)

Prospective, single center,

uncontrolled (historical

control from NIH PPH

registry)

High-dose CCBs were used in

patients who were

‘‘responders’’

(Note: Mean dose of nifedipine

was 172 � 41 mg/d,

and of diltiazem was

720 � 208 mg/d)

Up to 5 y,

University

of Illinois

Patients who were ‘‘responders’’ as defined by

patients who had a fall in PAP and PVR by

20% after acute CCB challenge (26% of all

patients) were treated with high-dose CCB.

Treated patients had much better 5-y survival

rate (94% in treated responders versus 55%

in nonresponders)

Survival of responders was much better than

historical control from NIH PPH registry

patients (in which vasoreactivity status was

not known) at the same institution

This st

PPH

scan

47% o

nonu

The res

and

mor

for d

Barst et al,

1999

Retrospective, single center

Review of medical records

All patients from

1982–1987,

Patients who were ‘‘responders’’ (31 responders out

of 74 tested; ie, 42%) were treated with high-dose

ter than

al rates were

responders

vely, in

re also

’’Responders’’ were defined as patients who had

a fall in PAP and PVR by 20%, no change or

increase in cardiac index, no change or decrease

in PVR/SVR ratio, after acute testing with

prostacyclin

Warfarin was started in all the patients in mid-1980s

when the adult studies showed survival benefit

going acute

CCB

were in

B

:

e numbers

er): Higher

in

nd lower

cute

sus

!65%

reached

!6.7 wood

activity

(OR: 7.35),

ctivity

R: 6.13),

(OR: 4.24),

in PVR of

index of

nce of class

3.02)

‘‘Responders’’ were defined as patients who had

a fall in both PAP and PVR by 20%, after acute

testing with IV prostacyclin (until 1994) on

inhaled NO (after 1994); 70 of 557 (12.6%)

were vasoreactive; 38 of 70 (ie, 6.8% of all 557)

were long-term CCB responders

The long-term CCB responders had less severe

baseline PAH (PVR 10.3 � 4.6 versus

14.9 � 5.3 wood units, CO 5.0 � 1.5 versus

3.9 � 1.1 L/min). At acute testing they had

more pronounced fall in mPAP (�39 � 11 versus

�26 � 7 mm Hg) and their mPAP reached

a lower absolute value (33 � 8 versus

46 � 10 mm Hg) compared with nonresponders

101

STANDARD

THERAPIE

SFOR

PAH

[33] (77) of pediatric patients with

PPH (mean age 7 years)

(range: 7 mo–13 y)

Columbia

University,

New York

Median

follow-up:

47 mo (range:

24–166 mo)

CCB. Survival of responders was bet

nonresponders (1-, 3-, and 5-y surviv

97%, 97%, and 97%, respectively, in

versus 66%, 52%, and 35%, respecti

nonresponders). 6 nonresponders we

treated with CCB in this study

Sitbon et al,

2005 [32]

(557)

Retrospective, single center

Review of medical records

of patients with IPAH

All IPAH patients

from

1984–2001,

Universite

Paris-Sud,

Clamart

France

Median

follow-up:

30 � 28 mo in

nonresponders

and 7 � 4.1 y

in responders

Only 6.8% of all IPAH patients under

vasoreactivity testing are long-term

responders, defined as patients who

NYHA class I or II after 1 y of CC

monotherapy

Predictors of long-term CCB response

On multivariate analysis: (although th

are too small to reach sufficient pow

baseline mixed venous oxyhemoglob

saturation (69 � 8 versus 61 � 8), a

PVR absolute value reached after a

vasoreactivity testing (5.2 � 2.7 ver

8.6 � 3.3 wood units)

On univariate analysis: baseline SVO2

(OR: 19.18), absolute value of PVR

post- acute vasoreactivity testing of

units (OR: 7.35), post- acute vasore

testing fall in mPAP fall of O31%

absolute value of post-acute vasorea

testing on mPAP of !37 mm Hg (O

baseline PVR of !11.5 wood units

post-acute vasoreactivity testing fall

O45% (OR: 3.27), baseline cardiac

!2.5 L/min/m sq. (OR: 3.21), abse

III or IV dyspnea at baseline (OR:

N ¼ Number of subjects.

102 ALAM & PALEVSKY

Table 4

Prothrombotic abnormalities in pulmonary arterial hypertension

Abnormalities Subjects Reference

I Platelets aggregation related

Urinary thromboxane metabolite (11 dehydroxy TxB2) IPAH [115]

Urinary PGI2 metabolite (PGI-M) IPAH [115]

Thromboxane A2 IPAH [115]

Prostacyclin IPAH [115]

Nitric oxide (exhaled or urinary excretion) IPAH, APAH [85]

Circulating platelet aggregates APAH [86]

Plasma serotonin, platelet serotonin IPAH [87,88]

Plasma-P selectin IPAH [94]

Thrombomodulin IPAH [89,94,99]

II Endothelial function related

Endothelial NO synthase IPAH [90]

Prostacyclin synthase expression IPAH [116]

Urinary PGI2 metabolite (PGI-M) IPAH [115]

Urinary thromboxane metabolite (11 dehydroxy

TxB2)

IPAH [115]

Thrombomodulin IPAH [89,94,99]

VWF IPAH, APAH [91,99]

Fibrinogen inhibitor plasminogen activator 1 IPAH [92,99]

III Coagulation and fibrinolytic proteins related

Prevalence of antiphospholipid

antibody/lupus anticoagulant

IPAH, CTE-PHT [93]

vWF antigen level IPAH [91,99]

Fibrinogen inhibitor

plasminogen activator 1

IPAH [92,99]

Euglobulin lysis time IPAH [99]

Fibrinogen level APAH [99]

Theoretical concerns about importance ofthromboembolism are supported by various early

observations (Table 5) [24–26,99,100].Retrospective [27,28,101] clinical studies and a

small prospective [29], noncontrolled, nonrandom-

ized clinical study of PPH patients has shown thatuse of anticoagulation with warfarin seems toconfer a survival advantage in patients who have

PPH (Table 6) [27–29,101–103]. In PAH, otherthan IPAH, the evidencedeither basic science orclinicaldfor or against the use of anticoagulation

is even scarcer (with the exception of CTE-PHT,in which the need for chronic anticoagulation iswell established). Because there are many similari-ties in the clinical course, hemodynamics, and his-

topathology of these and IPAH patients, thepractice of anticoagulation has been extended toother forms of PAH. It should be noted, however,

that the risk of bleeding complication (Table 7)and need for anticoagulation (Box 2) may differ inother causes of APAH [104].

There are no data from human studies as towhether there is any difference in terms of efficacy

among various anticoagulation agents such aswarfarin, unfractionated heparin, or low molec-

ular weight heparins. Warfarin is the mostcommonly used agent for anticoagulation inpatients who have PAH. Substantial data from

animal studies suggest that heparin may havesome additional therapeutic advantage in subjectswith PAH. Human studies, however, have not

been performed to support this theoretical supe-riority. Heparin has been shown to preventdevelopment of PAH and RV hypertrophy in

animal models (hypoxic mice or guinea pig modelof PAH) [105,106]. The mechanism of action ofheparin on pulmonary vasculature is not com-pletely understood. Proposed mechanisms include

inhibition of platelet-derived growth factor [105]and inhibition of pulmonary artery smooth mus-cle cell growth, probably by upregulation of

expression of cell cycle regulation of gene p27,which influences the level of cyclin-dependent ki-nase inhibitor [107]. Cyclin-dependent kinase and

cyclin-dependent kinase inhibitor play key rolesin the balance between cell proliferation and

103STANDARD THERAPIES FOR PAH

cell quiescence. Research also has shown in ani-mal models that anticoagulation with warfarindoes not have the same effect as that of heparinto protect animals from developing PAH upon

prolonged exposure to hypoxia [108]. O-hexanoyllow-molecular-weight heparin derivatives havebeen shown to be more effective in growth inhibi-

tion of bovine pulmonary artery smooth musclecells in culture than heparin [109]. Because ofsuch observations, the authors concluded that

heparin derivatives may be envisioned as poten-tial future PAH therapy. Currently, there areno human clinical data to support the use of hep-

arin or heparin derivatives instead of warfarin inpatients who have PAH.

In clinical practices, warfarin has been theagent most frequently used. Target international

normalized ratio (INR) in most US centers isbetween 1.5 and 2.5 and in many Europeancenters it is 2.0 to 3.0. Both approaches are based

on expert opinions, weighing potential benefits oftherapy versus risk of bleeding complications withhigher target INR [110]. It may be appropriate to

keep INR O 2.0 in the following situations:

1. In any patient in whom there exists a clinical

indication for anticoagulation (eg, atrialfibrillation, CTE-PHT, acute recent venousthromboembolism, or prosthetic valve)

2. In patients with remote history of idiopathicvenous thromboembolism

3. In patients in whom ventilation-perfusion(V/Q) scans or PA angiograms are not con-

sistent with chronic pulmonary thromboem-bolic disease (CPTED) but who have at

Box 2. Pulmonary arterialhypertension–associated conditionsin which anticoagulation managementis dictated by principalsof the associated disease

CTE-PHT (also consider inferiorvena-caval [IVC] filter)

Mitral or other valve prosthesisHigh-risk atrial fibrillationOsler-Weber Rendu syndrome and

similar diseases with history ofischemic strokes or transient ischemicattacks

Lupus anticoagulant syndrome or otherprocoagulant states

least one subsegmental mismatched defector diffusely decreased tracer uptake in certainsubsegments or in whom PA angiograms areunequivocal for the absence of CPTED

4. In patients with history of ischemic stroke ortransient ischemic attack with known right-to-left shunt

The role of antiplatelet agents such as aspirinand clopidogrel has not been thoroughly evaluated.

A recent preliminary randomized, double-blind,placebo-controlled, crossover study of 19 patientswho have IPAH explored the biochemical effects of

clopidogrel and aspirin on inhibition of plateletaggregation eicosanoid metabolism [111]. Thestudy represents the first well-structured, placebo-

controlled trial to evaluate biochemical effects ofantiplatelet agents in patients who have IPAH.The study showed that both drugs inhibit platelet

aggregation in patients who have IPAH. Arachi-donic acid–induced platelet inhibition was morecompletely blocked by aspirin, whereas ADP-induced platelet aggregation was more effectively

blocked by clopidogrel. Only aspirin inhibitedthromboxane metabolite production without af-fecting prostaglandin I2 metabolite synthesis, thus

restoring normal eicosanoid balance.Empiric anticoagulation may be considered

if clinical suspicion of PAH is moderate to high

and an echocardiogram shows an estimated pul-monary artery pressure O60 while the patientis undergoing evaluation [112]. When an interrup-tion in anticoagulation therapy is required, such

as before a surgical procedure, in the absence ofany other indication for anticoagulation warfarinmay be stopped 5 to 7 days before the procedure

and restarted after the procedure when the in-creased risk of bleeding has resolved, withoutany overlap with intravenous heparin or subcuta-

neous low molecular weight heparin. When theINR is !1.5, appropriate deep venous thrombo-sis prophylaxis should be instituted when patients

are hospitalized or as appropriate for the patient’sclinical status [113].

Calcium channel blockers

The hallmark of PAH is increased PVR, whichcompromises the ability of the right ventricle to

maintain cardiac output [3]. Increased RV strokework (volume of blood pumped � pressureagainst which the volume is pumped) against the

abnormally increased PVR has been thought tobe the cause of RV hypertrophy and dilatationand, eventually, failure to pump effectively

Tab

Obs

Stud

[refe Comments

Wag

19

The criteria for calling a biopsy consistent with

CPTED may or may not correctly identify

CPTED cases

It is not clear whether all of these patients were

evaluated by V/Q scan or pulmonary artery

angiogram before the biopsy

Bjor

19

Mean age for primary pulmonary arteritis on

biopsy was 16 years and 21–34 years for

plexogenic pulmonary arteriopathy, primary

medial arteriopathy, and pulmonary

veno-occlusive disease versus 41 years for

patients with thromboembolic disease

Biopsy specimens were taken from tissue registry

(73 autopsies, 6 open lung biopsies, 1 both)

Loy

19

(F

PA

The study represents one of the most insightful

reviews of pathologic changes in PAH

Authors concluded that coexistence of thrombotic

and plexiform lesions within the same family

and individual represents that these lesions are

not specific but they represent different

manifestations of the same initial pathologic

process

These lesions are probability two different

outcomes of a single starting pathologic process

in a disease caused by autosomal dominant

inheritance pattern

The differentiation of these lesions may depend on

the anatomic location of the lesion, other

factors in the local lung environment, or

a random phenomenon

104

ALAM

&PALEVSKY

le 5

ervations suggesting role of thrombosis in patients who have idiopathic pulmonary arterial hypertension

y

rence] (N) Design method Study findings

envoort,

80 [24] (72)

Retrospective

Review of lung biopsy specimens

from patients with pulmonary

vascular disease

12/40 (30%) patients with unexplained PAH had

evidence of CPTED (ie, severe eccentric intimal

fibrosis) in the absence of concentric lesions

nsson et al,

85 [25] (85)

Retrospective

Review of lung biopsy specimens

from patients with clinical

diagnosis of PPH from

1930–1983 at Mayo Clinic

56% of the patients had biopsies consistent with

thromboembolic disease

d et al,

88 [100]

amilial

H: 23)

Retrospective

Review of histopathology of

postmortem lung sections 23

members of 13 families with

familial PAH; pathologists were

blinded to patient and family

identity; every artery and

abnormal vein was categorized by

adopted WHO classification that

was used in pathology core NIH

PPH registry

2516 vessels (28–264 with mean of

109 � 62 SD per patient) were

described

Quantitative description was reported

18/23 (78%) patients from 12/13 (92%) families

had vessels with organized thrombi

18/23 (78%) patients from 12/13 (92%) families

had plexiform lesions

2.7% of all arteries had organized thrombi

3.4 of all arteries had plexiform lesions

15/23 (65%) patients had coexisting plexiform and

thrombotic lesions

There was no correlation between type of lesion or

percent of arteries with plexiform lesions

between age of patient or survival in this study

105STANDARD THERAPIES FOR PAH

Pietraet

al,

1989[26](58)

Retrospective(althoughpatientswere

identified

prospectively)

Review

ofhistopathologyoflung

biopsy,pneumonectomy,or

autopsy

specim

ensfrom

PPH

patients

inNIH

/NHLBIregistry

ofPPH

patients

19/48(40%)patients

whohadluminalorintimal

lesionshadthromboticlesionsasdefined

by

both

recanalizedthrombiandeccentric

intimal

fibrosiswithoutplexiform

lesions

9/25(36%)patients

withplexiform

lesionsalso

hadrecacalizedthrombi

Prognosisofpatients

withthromboticlesionswas

much

betterthanforpatients

withplexiform

lesionsorveno-occlusivedisease

NOTE:theNIH

registry

onlyincluded

patientswith

lowprobab

ilityV/Q

scansornorm

alpulm

onary

arteryangiogram;allpatientswererequired

to

haveV/Q

scanorpulm

onary

angiogram

Welsh

etal,

1996[99](PPH:

12,SPH:25,

Control:15)

Cross-sectional

Plasm

asamplesofPPH,SPH,and

age-matched

controlswere

collectedandmultiple

coagulation

relatedparameterswerestudied

Comparedwiththecontrolgroup

InPPH

patients:

�Thrombomodulinlevelsweredecreased

�Fibrinolyticinhibitorplasm

inogen

activator-I

wasincreased

�Euglobulinlysistimewasincreased

InSPH

patients:

�VonWillebrandfactorwasincreased

�Fibrinogen

level

wasincreased

Lower

fibrinolyticactivitycorrelatedwithhigher

meanpulm

onary

arterypressures

Whether

decreasedfibrinolyticactivityisaneff

ect

oforcause

ofelevatedmeanpulm

onary

artery

pressure

isnotclear

N¼

Number

ofsubjects.

(maintain cardiac output) against increasing resis-tance. The idea of attempting to decrease PVR inPAH by vasodilation has always been tempting[114]. Multiple basic science experiments and clin-

ical studies suggest that in animal models of PAHand in patients who have PAH, the mediators ofpulmonary vasodilation are decreased, whereas

the mediators of vasoconstriction are overex-pressed [115–117]. Clinical studies indicated thatthe ability to successfully produce vasodilation

by certain agents with known vasodilator proper-ties (eg, CCBs [118], IV prostacyclin [119,120],inhaled NO [121–124], IV adenosine [125], or

inhaled iloprost [126]) in patients with PPH iden-tifies the patients who have much better prognosis[29,32–34,127], particularly if they are treated withhigh-dose CCBs (Table 3) [29,32–34]. Such testing

(known as acute vasoreactivity testing [Table 8])became a routine for almost all patients whohave PAH and are undergoing initial diagnostic

right heart catheterization, except patients withlow cardiac output or concurrent left heart failure,as indicated by elevated pulmonary capillary

wedge pressure. Patients who have significant(see Table 6) pulmonary vasodilation withouta significant systemic vasodilation (as assessed

by change in PVR/SVR ratio or clinically unac-ceptable fall in systemic blood pressure) in acutevasoreactivity testing are called ‘‘responders’’and are candidates for long-term CCB therapy.

The current definition of a responder is a decreasein mean pulmonary arterial pressure of O10 mmHg to a mean pulmonary artery pressure of %40

mm Hg with a maintained (or increased) cardiacoutput. ‘‘Responders’’ comprise 10% to 26% ofIPAH patients undergoing such testing; unfortu-

nately, the proportion of patients who are re-sponders among APAH (eg, scleroderma orCTE-PHT) is even lower [128]. The role of acutevasoreactivity testing and the use of CCBs in pa-

tients who have APAH who demonstrate acutevasodilation are not known.

There are reports of patients who have IPAH

and who were initially nonresponders to acutevasoreactivity testing, transforming to respondersat repeat right heart catheterization after pro-

longed use of IV prostacyclin [129]. No data areavailable to define the safety or role of CCBs insuch patients. A recent report suggests that only

a small minority (6.8%) of all patients who havePAH can be managed by CCBs in the long-termwithout need for additional specific PAH therapy,because as many as half of the patients on CCBs

deteriorate in the subsequent years [32]. Because

Comments

Improved survival on anticoagulation was

noted in thromboembolic and plexogenic

arteriopathy, but numbers were too small

to reach statistical significance (to ascertain

statistical power)

The criteria for deciding not to anticoagulate

are not clear and might have introduced

a selection bias

This study also involved use of high-dose

CCB in patients who were ‘‘responders’’ as

defined by patients who had a fall in PAP

and PVR by 20% after acute CCB

challenge

47% of responders and 57% of

nonresponders had nonuniform perfusion

of V/Q scans Patients with high probability

V/Q scans were excluded from the study

Contrary to most studies cited in this table,

this study showed no difference in survival

in first 5 y of follow-up of anticoagulated

and nonanticoagulated PPH patients. In

the following 5 y, some survival advantage

was noted in anticoagulated PPH group

that did not reach statistical significance.

NOTE: the study included only 24 PPH

patients who received anticoagulation

106

ALAM

&PALEVSKY

Table 6

Clinical studies: anticoagulation and pulmonary arterial hypertension

Study

[reference] (N) Design method

Follow-up duration,

site Study findings

Fuster et al,

1984 [27]

(120)

Retrospective, single

center

Review of medical

records of patients

with PPH diagnosis

by clinical and

hemodynamic criteria

PPH patients from

1955–1977 who

were followed up

until 1983 at

Mayo Clinic, with

minimum

follow-up of 5 y

(median 14 y,

longest 27 y) or up

to death

Of 56 patients who underwent autopsy, 57%

patients had changes consistent with only

thromboembolic PH in the absence of

plexogenic pulmonary arteriopathy

Patients who were treated with

anticoagulation as defined by initiation

within 1 y of diagnosis had significantly

better 3-y survival (49% versus 21%)

compared with those who were not

anticoagulated

Rich et al,

1992 [29] (64)

Prospective,

uncontrolled, single

center (historical

control from

NIH PPH registry)

Warfarin was given to all

PPH patients with

nonuniform perfusion

on V/Q scan (55% of

all)

Up to 5 y,

University of

Illinois

Warfarin use was associated with improved

survival, particularly in patients who were

nonresponders to high-dose CCB (1-y

survival: 91% versus 62%, 3-y survival:

47% versus 31%) when compared with

historical control from NIH PPH registry

Frank et al,

1997 [101]

(173)

Retrospective, two

centers were involved

Review of medical

records of patients

with PPH (total 64, 24

received warfarin) and

anorectic

drug-induced PAH

(total 104, 56

received warfarin)

Approximately up to

10 y, University of

Vienna and

University of Bern

Anticoagulated aminorex-treated patient had

better mean survival compared with

nonanticoagulated aminorex-treated

patients (8.3 versus 6.1 y)

Aminorex PHT patients who started receiving

anticoagulation therapy sooner had better

mean survival compared with patients who

stated treatment 2 y after diagnosis (10.9

versus 5.9 y)

Overall, patients treated with aminorex had

better mean survival compared with PPH

patients (7.5 versus 3.9 y)

107STANDARD THERAPIES FOR PAH

Kawutet

al,

2005[28](84)

Retrospective,

single

center

Review

ofmedical

recordsofpatients

withIPAH

(66),

familialPAH

(14),

anorexogen-related

PAH

(4)

Allconsecutiveadult

patients

with

initialevaluation

between1994and

2002,Columbia

University,New

York

(median

follow-up,764d)

Amongthepatients

treatedwith

anticoagulation(94%

ofall),

transplant-free

survivalwasim

proved

(hazard

ratio:0.35,95%

CI:0.12–0.90,

P¼

.05).

1-,3-,and5-y

transplant-free

survivalrates

were87%

,75%,and61%

,respectively,for

thewhole

cohort

Thecriteria

fordecidingnotto

anticoagulate

are

notclearandmighthaveintroduced

aselectionbiasa

N¼

Number

ofsubjects.

aNote:Thereare

other

less

structuredretrospectivestudiesorcase

series,someofwhichfavoranticoagulation[102,127]andothers[103]thatreported

nodifference

in

survivalamonganticoagulatedandnon-anticoagulatedpatients

whohavePAH.

of such reports and the availability of newer safeand effective oral and inhaled (rather than paren-teral) PAH therapies, the enthusiasm to supportthe necessity of acute vasoreactivity testing as an

essential part of PAH evaluation has somewhatdecreased. Currently, however, acute vasoreactiv-ity testing continues to be part of the algorithm

for the evaluation of patients who have PAH (par-ticularly IPAH). The predictors of long-term re-sponse to CCBs without the need for additional

agent are listed in Table 3 [32].It should be noted that 80% to 90% of all

patients who have IPAH and a greater percentage

of patients who have APAH are nonresponders atacute vasoreactivity testing, and these patients aretreated with specific PAH therapies (eg, prostacy-clin analogs, endothelial receptor antagonists, or

5-phosphodiestrase inhibitors). Importantly, thelack of response to acute vasoreactivity testing (ie,the administration of inhaled or IV prostacyclin,

NO, or adenosine) does not rule out the likelihoodof improvement with long-term use of prostacy-clins or other specific PAH therapies [4–21].

The primary purpose of acute vasoreactivitytesting is to determine whether CCBs could beused as PAH therapy. The CCBs are not used in

patients who have significant acute RHF becauseof cardiodepressor effects. There is no role of acutevasoreactivity testing in patients who have PAHwho are hospitalized with acute worsening of

RHF. Similarly, if at the time of right heartcatheterization (RHC) the cardiac output is de-termined to be low (CI !2.0) acute vasoreactivity

should not be performed because it will have noimpact on the treatment and it may be associatedwith an undesirable fall in systemic blood pressure

or cardiac output. In any patient, acute vaso-reactivity testing may precipitate acute pulmonaryedema and marked worsening of hypoxemia [130].It should be done with caution in patients who

have a pulmonary capillary wedge pressure ofR15 cm H2O. In the event of any sudden worsen-ing in oxyhemoglobin saturation during acute vas-

oreactivity testing, acute pulmonary edema shouldbe considered. The vasodilator agent should bediscontinued and treatment with intravenous mor-

phine, intravenous nitroglycerine, and furosemidemay be considered [130]. It should be noted thatacute severe pulmonary edema during acute vaso-

reactivity testing is not a contraindication to theuse of pulmonary vasodilator agents, such as in-travenous prostacyclin. This should be done withextreme caution, and dose escalation should be

done slowly [130]. Some authorities favor testing

anticoagulation

ts

ontinue anticoagulation if more than minimal

itor for hypochromic microcytic anemia, occult

iscontinue anticoagulation if significant

d; consider restarting anticoagulation after a few

minor and endoscopic findings are not alarming

ot anticoagulate patients with significant varices,

t variceal bleed, or moderate to severe

O1.4) or thrombocytopenia (platelet count

g interactions may be more pronounced

as in portopulmonary hypertension

e by 30%–40%; recheck INR in 7–10 days and

frequently until INR becomes stable, only at the

ation of Bosentan therapy

e by 80%, recheck INR in 7–10 days, and

frequently until INR becomes stable, only at the

ation of Sitaxsentan therapy

ended that all patients receiving PAH therapies

atheter should be anticoagulated. NOTE:

ave antiplatelet aggregation properties, and

upport such recommendation is lacking

globin more frequently, hold anticoagulation if

ay become bactremic secondary to ischemic

as many terminal patients with severe RHF do);

trum antibiotics covering enteric gram-negative

ld be continued at any cost in patients with

om PE is suspected cause of an isolated syncope;

, risks and benefits should be carefully weighed;

pace themselves may be the initial advice

108

ALAM

&PALEVSKY

Table 7

Associated pulmonary arterial hypertensive conditions and clinical circumstances with increased rate of complications from

Diseases/circumstances Caution Management commen

Congenital heart disease Massive hemoptysis is cause of death in many patients Extreme caution; disc

hemoptysis

Scleroderma Risk of gastrointestinal bleed secondary to telangiectesias Extreme caution; mon

blood, or malena; d

gastrointestinal blee

months if bleed was

Portopulmonary hypertension Many patients have coagulopathy and/or

thrombocytopenia; many have varices

Extreme caution; do n

history of significan

coagulopathy (INR

!40, 000/mL); dru

HIV Many patients have thrombocytopenia; many have

concurrent advanced liver disease; HAART therapy

may have drug interaction

Similar cautions apply

Bosentan therapy Increases warfarin dose requirement Increase warfarin dos

monitor INR more

initiation or termin

Sitaxsentan therapy Decreases warfarin dose requirement Decrease warfarin dos

monitor INR more

initiation or termin

Intravenous prostacyclin or treprostinil Risk of central venous catheter–related clot and risk of

clogging of the catheter lumen secondary to low flow

rate of infusion

It is generally recomm

via central venous c

prostacyclins also h

direct evidence to s

Severe RHF Passive hepatic congestion may cause coagulopathy

or ischemic bowl

Check INR and hemo

necessary; patient m

colonic ulcerations (

consider broad-spec

rods and anaerobes

Syncope Syncopal and presyncopal episodes are common

in patients who have severe PAH

Anticoagulation shou

CTE-PHT or in wh

in all other patients

advising patients to

109STANDARD THERAPIES FOR PAH

Pregnancy

Warfarinisteratogenic

andis

contraindicated(C

lass

D)in

pregnancy

Pregnancy

carriesahighrisk

ofmortality

(30%–50%

)in

patientswith

moderate

toseverePAH;allfemale

PAH

patients

ofreproductive

potentialshould

beadvised

toobservestrict

contraception;

term

inationofpregnancy

should

bestrongly

advised

inpatientswho

dobecomepregnant;if,however,apatient

does

insist

oncontinuingpregnancy,LMWH

should

beused

Acute

illness,antibioticuse,sepsis

Relativevitamin

Kdeficiency

relatedto

antibiotic

use

orpoororalintakemayprolongIN

R;

sepsismaycause

coagulopathyand/or

thrombocytopenia

Consider

transientlyholdinganticoagulationwhileusingsystem

ic

compressiondevices

(SCDs)

fordeepvenousthrombosis

prophylaxis;consider

oralorsubcutaneousvitamin

K

supplementation

with IV nitroprusside [131] in patients with highpulmonary capillary wedge pressure. A fall in sys-temic arterial blood pressure with IV nitroprussidecausing increase in cardiac output and drop in pul-

monary capillary wedge pressure highly suggeststhe possibility of concurrent LV diastolic dysfunc-tion. Similarly, in patients with pulmonary veno-

occlusive disease, the acute vasoreactivity testingmay result in massive pulmonary edema, whichmay even be fatal. Death has been reported in a pa-

tient with pulmonary veno-occlusive disease asa result of administration of IV prostacyclin[132] at 2 ng/kg/min for only 5 minutes.

Inhaled NO, inhaled prostacyclin, IV prostacy-clin, or IV adenosine may be used for acute testing[35–37]. These agents are short acting, easily ad-ministered and titrated, have minimal systemic

effects at doses that can result in pulmonary arterialvasodilation, and demonstrate rapid reversal of ef-fects if complications ensue. The CCBs should not

be used for this testing because they are longer act-ing and their use may be associated with complica-tions such as systemic hypotension and worsening

of hypoxemia. These reactions to CCBs were pri-marily seen in patients who were actually nonre-sponders. Because of little likelihood of benefit

and a risk of side effects and complications, empiricuse of CCBs in all patients who have PAH withoutknowing acute vasoreactivity status is not indi-cated, is dangerous, and may be fatal.

In only a small subset (10%–26%) of patientswho are responders and have no specific contrain-dication to CCBs, these agents may be started as an

inpatient treatmentwith PAcatheter in place (acuteCCB dose escalation) or by slowly increasing thedose on an outpatient basis (see Table 8). The

choice of agent depends on the resting heart rateof the patient [29,32–34]. If the patient’s heart rateis O100 beats/min, diltiazem is used; if the heartrate is !100 beats/min, nifedipine is used. Verapa-

mil is generally not used because of its strong cardi-odepressor properties. Amlodipine is anotherchoice, especially for patients who cannot tolerate

the other CCBs secondary to side effects, such asworsening of peripheral edema, systemic hypoten-sion, or abnormally low or high heart rate.

Summary

After half a century of clinical experience andresearch, PAH management remains a challenge.

Currently, data to support the use of standardPAH therapies (eg, oxygen supplementation, di-uretics, digoxin, anticoagulation, and CCBs) are

110 ALAM & PALEVSKY

Table 8

Use of calcium channel blockers in pulmonary arterial hypertension

Indications

� PAH patients with WHO group I and

� PAH diagnosis confirmed on right heart catheterization

(ie, PVR above 3.0 wood units by Fick’s method) and

� ‘‘Responder’’ on ‘‘acute vasoreactivity testing’’

Contraindications

� Low cardiac output, cardiac index !2.0

� Severe RHF

� Hypotension, systolic BP below 90 mm Hg

� History of adverse reaction or intolerance to CCB

Cautions

� Empiric trial of CCB without acute vasoreactivity

testing should not be performed. It is unsafe and may

cause hypotension [125] and even death [124]

� Acute vasoreactivity testing should not be performed

with CCB because it is unsafe and may cause profound

hypotension, acute pulmonary edema, and potentially

death

� Patients who are acutely decompensated with RHF

are not candidates for CCB therapy. There is no real

reason to perform acute vasoreactivity testing in such

patients

Acute vasoreactivity testing

A. Agents used [121–127]

� Inhaled NO: 20 ppm for 6–10 minute by face mask

� IV prostacyclin: Start 1 ng/kg/min; increase by

1–2 ng/kg/min every 5–15 min to maximum

of 12 ng/kg/min or untolerable side effects or

2.5 ng/kg/min, increase by 2.5 ng/kg/min every

10 min to maximum of 12 ng/kg/min; mean

tolerated dose: 8 ng/kg/min

� Inhaled prostacyclin:50 ng/kg/min via nebulizer

for 15 min

� IV adenosine: fast IV bolus 50 mg/kg/min; increase

by 50 mg/kg/min every 2 min to maximum

of 500 mg/kg/min

B. Criteria for significant response (‘‘acute responder’’)

� Drop in mPAP O10 mm Hg

or Attaining an mPAP !40 mm Hg

or Decrease in PVR by R20%

or Attaining a PVR !8 wood units

� and Increase or no decrease in cardiac output

� and No or only clinically acceptable fall in systemic

blood pressure

� NOTE: there are no universally accepted criteria

[35–37]

Practical use of CCBs

Choice and dose of calcium channel blockers

� Chose nifedipine if baseline resting heart rate

!100/min and diltiazem if O100/min

� Amlodipine may be used if significant side effects

from other agents (eg, worsening edema, significant

tachycardia, bradycardia, or hypotension)

� Verapamil should not be used secondary to strong

cardiodepressor effects

� Generally high doses are required (eg, nifedipine

up to 240 mg/d and diltiazem 720 mg/d, both in three

divided doses, amlodipine up to 5 mg twice a day

� Only oral administration is used

Initiation of CCB

CCB may be started in either inpatient setting or outpatient setting

(there are no rigid recommendations,

and approaches may vary among different centers)

A. Inpatient setting: rapid CCB dose escalation

� All rapid CCB dose escalations are generally performed with

PA catheter in place

� Patients receive initial dose of nifedipine 10–20 mg orally or

diltiazem 60 mg orally; hemodynamic measurements are

obtained in 1 h

� The dose and hemodynamic measurements are repeated

every hour until a ‘‘threshold’’ response (fall in PVR by 50%

and, not or, fall in mPAP by 33%) is achieved or significant

side effects are experienced (eg, hypotension [mBP !90 mm

Hg], gastrointestinal upset [nausea, vomiting])

� Total daily dose is calculated by adding up total amount of

drug administered during this testing. The goal is to achieve

this in three divided doses (four to six divided doses if

significant side effects)

� Patient is then given nifedipine 20 mg orally three times daily

or diltiazem 60 mg orally three times daily next day and is

discharged

� The dose is then gradually increased to the desired level

(as estimated previously) over a period of 6–12 wk while

frequently monitoring BP and heart rate

B. Outpatient setting: slow CCB dose escalation

� Patients are started on initial dose of nifedipine 10–20 mg

orally three times daily or diltiazem 60 mg orally three times

daily

� The dose is then gradually increased with a goal to

ultimately achieve the maximum dose (nifedipine

240 mg/d or diltiazem 720 mg/d, both in three divided doses;

amlodipine up to 5 mg twice daily) over a period of 6–12 wk,

while frequently monitoring the BP and heart rate. If patient

experiences limiting side effects (as mentioned previously)

before the maximum dose is reached, either the dose is kept

at that level or further increase is achieved by increasing the

dose frequency to every 4–6 h

Follow-up, when to use additional therapies

� Only 6.8% of all patients who have PAH are long-term

responders to CCB (ie, who will be in NYHA I or II on

monotherapy with CCB for 1 y) [32]

� Approximately half of the patients who are responders at

initial acute vasoreactivity testing and are placed on CCB

require an additional PAH therapy within 1 y

� Secondary to this risk of failure of CCB monotherapy, such

patients should be closely followed (every 3–6 mo) and

should be started on an additional therapy if there is clinical

worsening or worsening of 6-minute walking distance.

� Secondary to this risk of failure of CCB monotherapy, some

experts consider adding a specific PAH agent at the

beginning, especially in patients who have poor predictors

of long-term response at baseline hemodynamics and

vasoreactivity testing [32]

111STANDARD THERAPIES FOR PAH

mostly retrospective, uncontrolled prospective, orderived from other diseases with similar but notidentical manifestations. In the absence of anyfurther prospective, controlled studies, it is rea-

sonable to use these therapies when they aretolerated. When these therapies are poorly toler-ated, however, the threshold for discontinuation

should be low.

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