Long-Term Effectiveness of Extended-Release Nitrate for
`the Treatment of Systolic Hypertension
`
`Gordon S. Stokes, Alexandra J Bune, Natasha Huon, Edward S. Barin
`
`Abstract—lIsosorbide mononitrate ISMN) iseffective in the short-term for decreasing systolic blood pressure, pulse pressure,
`and pulse wavereflection in patients with systolic hypertension. To determine whether tolerance negates the efficacy ofthis
`nitrate in the long-term, a placebo-controlled study was performed in which ISMN was withdrawn briefly in a group of
`patients (n=16) who had received extended-release ISMN 60 to 120 mg once daily for 16 to 109 months. Blood pressure and
`wavereflection were determined by 24-hour ambulatory recorder and tonometer, respectively. During a 4-hour delay of the
`regular morning dose of ISMN, mean systolic blood pressure was higher than with the regular ISMN dosing schedule
`(P<0.0001). The maximum placebo-active difference was 16+4 mm Hg. The corresponding difference in augmentation
`index (a measure of pulse wavereflection) corrected for heart rate was 25+4% (P<0.001). The difference in pulse pressure
`was 13+3 mm Hg (P<0.001). There was no significant difference in diastolic blood pressure. For a subgroup (n=12) in
`which the effects of a single ISMN dose had been determined atthe initiation of regular ISMN therapy, the mean change in
`augmentation index was of similar magnitude to that observed in their initial study. Thus, tolerance does not seriously
`diminish the antihypertensive efficacy of ISMN used as adjunct therapy in the chronic treatment of systolic hypertension. This
`agent lowers systolic blood pressure sufficiently to achieve therapeutic goal in some patients refractory to conventional
`treatment regimens. (Hypertension. 2005;45:380-384.)
`
`Key Words: antihypertensive therapy m hypertension m arterial pressure m nitric oxide
`
`
`
`1707‘£1ArenigajuoAqSio‘sjeumnofeye//:dyywopopeopumog
`
`ncontrolled systolic hypertension is an important risk
`factor for stroke and heart attack in the elderly andis often
`refractory to treatment with established antihypertensive agents.!
`Characteristic of this condition is a high arterial pulse pressure
`that results from effects of aging and age-associated cardiovas-
`cular disease on the arterial wall.? With advancing age, there is
`large artery stiffening that reduces arterial compliance and
`increasesthe velocity of transmissionofthe reflected component
`of the pulse wavesothat it moves in timing from diastole to late
`systole.? Additionally, there is small artery constriction that
`increases the magnitude ofreflection. The reflection combines
`with the ejection componentof the pulse wave, thereby boosting
`pulse pressure and systolic pressure.
`The changes in arterial wall function may derive from
`endothelial dysfunction,‘ including deficiency in endogenous
`nitric oxide generation.>.° Exogenous nitrate has been shown
`to reverse these changes,
`resulting in increased arterial
`compliance, vasodilatation, and decreased systolic blood
`pressure.? An attractive concept, articulated more than a
`decade ago’ andstill topical,° is that nitric oxide donors could
`be administered therapeutically in hypertensive patients to
`obtain a predominant decrease in systolic blood pressure.
`Such an effect has been reported from short-term trials in
`elderly patients with isolated systolic hypertension using
`extended-release formulations of either isosorbide dinitrate or
`
`isosorbide mononitrate (ISMN).!°-!5 However, evidence for
`long-term antihypertensive efficacy with ISMN is rather
`limited,1-15 and there have been no controlled trials to deter-
`mine whether ISMN exercises a preventative effect on
`morbid cardiovascular events in hypertension.
`It has been argued that tolerance to the actions of nitrates
`like ISMN may appear if they are used long-term to treat
`arterial insufficiency states such as angina pectoris.16 How-
`ever,
`tolerance was not detected with isosorbide dinitrate
`whenusedto treat systolic hypertension in the elderly.1” For
`9 years, we have used ISMNasan adjunctin treating selected
`patients with refractory systolic hypertension. Werecalled a
`group of these patients and determined in a randomized
`crossover study against placebo whether ISMN exhibited
`long-term antihypertensive efficacy. Also, we determined
`whether the effects on arterial pulse wave reflection and
`arterial stiffness, which are characteristic of ISMN,persisted
`with long-term ISMN treatment.
`
`Subjects and Methods
`The subjects were 16 elderly patients with long-standing hyperten-
`sion. All were fully ambulant without symptomatic cardiac disease
`or known vascular aneurysm. One subject had a history of unilateral
`renal artery stenosis successfully treated by angioplasty and 1 had
`mild primary aldosteronism without adrenal lateralization; in the
`remainder, causes of secondary hypertension had been excluded by
`
`Received September 13, 2004; first decision September 17, 2004; revision accepted November 19, 2004.
`From Hypertension Unit, Royal North Shore Hospital, St Leonards, NSW, Australia.
`Correspondence to G.S. Stokes, Hypertension Unit, Block 1B, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia. E-mail
`gstokes @med.usyd.edu.au
`Human Power of N Company
`© 2005 American Heart Association, Inc.
`DOI: 10.1161/01.HYP.0000156746.25300.1¢
`
`Hypertension is available at http://‘www.hypertensionaha.org
`
`EX1023
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`Human Power of N Company
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`

`TABLE 1. Patient Characteristics
`
`Clinical Data
`
`Total
`
`No.
`
`16
`
`%
`
`100
`
`Age (mean [range]), y
`Men
`Previous ischemic heart disease
`Previous stroke
`Treatment with HMG CoA reductaseinhibitors
`
`72 [64-83]
`7
`4
`2
`8
`
`Pre-ISMN antihypertensive therapy*
`Combination of 2 agents
`Combination of 3 agents
`
`Combination of 4 agents
`Dose of ISMN (as adjunct)
`60 mg per day
`120 mg per day
`
`6
`6
`
`4
`
`7
`9
`
`44
`25
`12.5
`50
`
`37.5
`37.5
`
`25
`
`44
`56
`
`*Two to 4 agents, each from a different class: diuretic (n=14), 8 blocker
`(n=7), calcium channel blocker
`(n=12), angiotensin-converting enzyme
`inhibitor (n=4), angiotensin Il receptor blocker (n=8), sympatholytic (n=1).
`
`routine screening tests. Plasma creatinine concentration was
`<0.15 mmol/L in every case. Further characteristics are shown in
`Table 1. Eight patients receiving treatment with 3-hydroxy-3-
`methylglutaryl coenzyme A reductase inhibitors for hyperlipidemia
`had a mean total serum cholesterol concentration of 4.7 mmol/L
`(range, 4.3 to 6.5). The remainder (n=8) had a mean total serum
`cholesterol concentration of 5.0 mmol/L (range, 3.5 to 6.3). All the
`subjects were referred from their family physicians after having
`undergone treatment with various regimens of conventional antihy-
`pertensive agents given singly and in combination; none of these
`regimens had controlled systolic blood pressure adequately. ISMN
`had been shown to provide an additional antihypertensive effect
`when added to the most effective of the antihypertensive regimens
`that was tolerated by the patient. The antihypertensive therapy
`immediately before starting ISMN (Table 1) consisted of 2 to 4 of the
`following drugs, administered in conventional dosage: diuretics
`(hydrochlorothiazide 25 to 12.5 mg/d [8 cases], amiloride 5 mg/d [2
`cases], indapamide 2.5 mg/d [3 cases], aldactone 50 mg/d [1 case]);
`B-blockers (atenolol 50 to 100 mg/d [4 cases], metoprolol 50 mg/d [1
`case], sotalo] 160 mg/d [1 case], pindolol 10 mg/d [1 case]); calcium
`channel blockers (amlodipine 5 to 7.5 mg/d [2 cases], lercanidipine
`5 to 10 mg/d [2 cases], controlled-release formulations of diltiazem
`240 mg/d [2 cases] or nifedipine 30 to 120 mg/d [6 cases]);
`angiotensin-converting enzymeinhibitors (ramipril 10 mg/d [1 case],
`perindopril 4 mg/d [2 cases], monopril 10 mg/d [1 care]); angiotensin
`I receptor antagonists (candesartan 4 to 32 mg/d[4 cases], irbesartan
`300 mg/d [3 cases], telmisartan 40 mg/d [1 case]); and sympatholytic
`(prazosin 2 mg/d [1 case]). Additionally, all patients had received
`extended-release isosorbide mononitrate, 60 to 120 mg in the
`morning, for a continuous period of 16 to 109 months (mean, 48
`months) up to the time of the present study.
`At least 1 week (usually 1 month) before the time of entry to the
`presentstudy, the dosing schedule of the antihypertensive therapy for
`each patient had been rearranged so that medication other than ISMN
`was taken in the late afternoon or evening. This regimen was
`continued unchanged as baseline treatment
`through the present
`study.
`
`
`
`1707‘£1ArenigajuoAqSio‘sjeumnofeye//:dyywopopeopumog
`
`170-
`4605
`B 150-
`® 150
`
`120-
`
`110-
`
`100-
`
`
`
`50- 40
`Ambulatorybloodpressure(m 60-
`
`Stokeset al
`
`Long-Term ISMN in Systolic Hypertension
`
`381
`
`day, the active ISMN dose was given at 8:05 aM, followed by a
`placebo at 12:05 pm (sequence A); on the other study day, the
`placebo was given at 8:05 AM and the active ISMN wasgiven at
`12:05 PM (sequence B). The rationale was that a 4-hour delay in the
`usual time of dosing would be sufficient to reveal the presence of
`ongoing effectiveness of the nitrate without exposing high-risk
`patients to undue increases in systolic blood pressure. Ambulatory
`blood pressure recording for a 24-hour period was commenced at
`4:00 pM on the day before each study day to determine by
`comparison between days the effect of the dosing delay (Figure 1).
`Between observations on study days,
`the subjects engaged in
`sedentary recreational activities in a temperature-controlled environ-
`ment. A light meal was given at 12:30 PM.
`The study was approved by the institutional ethics committee.
`Written informed consent was obtained from all subjects. Ambula-
`tory blood pressure was measured by an automated monitor (Med-
`itech, Budapest, Hungary). The monitor was set
`to record at
`30-minute intervals from 4:00 PM to 10:00 PM and from 6:00 AM to
`8:00 AM the next day, at hourly intervals overnight between 10:00 pM
`and 6:00 AM, and at 15-minute intervals from 8:00 AM to 4:00 PM.
`The average blood pressure for each hourly period was determined
`for use in data presentation and analysis. Brachial blood pressure
`(average of 3 readings) was also recorded by a sphygmomanometer
`to allow calibration of pulse wave tonometry; this was performed on
`the radial artery at 8:00 am, 12:00 PM, and 4:00 pM, with the patient
`seated. The aortic first peak pressure (P1) and reflection peak (P2)
`were determined from the aortic pulse waveform by computer
`software (SphygmoCor; AtCor Medical, Sydney, Australia), as
`previously reported.12 Augmentation index ([P2+P1] %) described
`the magnitude of wavereflection; values cited from published work
`were transformed from an alternative expression of the augmentation
`index ([P2—P1]+pulse pressure %). Statistical analysis was by
`repeated measures analysis of variance using PRISM (GraphPad
`Software Inc, San Diego, Calif} and post-hoc paired ¢ tests. Values
`given are mean+SEM.
`
`Results
`Mean 24-hour values for ambulatory systolic blood pressure
`and diastolic blood pressure were not significantly different
`between sequence A (13643 and 67+2 mm Hg,respec-
`
`yp Ay
`| Ayattwel
`
`Systolic
`
`~~ Sequence A
`
`--*-~ Sequence B
`
`Diastolic
`
`
`T
`T
`T
`T
`6 PM
`12 PM
`6 AM
`12 NOON
`
`OO
`
`80+a iylat!EE
`
`Protocol
`A double-blind randomized crossover study of ISMNand a placebo
`Figure 1. Mean values and SEM (n=16) for 24-hour ambulatory
`was performed in each subject. The dose of ISMN waseither 60 mg
`blood pressure (systolic and diastolic) with treatment on differ-
`or 120 mg ISMN (determined by the dosage used in preceding
`ent study days with sequenceA (active ISMN at 8:05 am and
`long-term therapy). Encapsulated single doses of ISMN (extended-
`placebo at 12:05 pm) and sequenceB(placebo at 8:05 am and
`telease preparation; AstraZeneca, Australia) were given on 2 study
`active ISMN at 12:05 pm). Dotted lines show times of ISMN/pla-
`cebo administration.
`days, each separated from the next by 1 to 2 weeks. On one study
`
`Clock time (hours)
`
`Page 2 of 5
`
`Page 2 of 5
`
`

`

`382
`
`Hypertension
`
`March 2005
`
`TABLE 2. Mean Values+SEM for Ambulatory Blood Pressure and Heart Rate for the Period
`8:00 am to 12:00 pm After a Dose of ISMN (Schedule A) or Placebo (Schedule B) at 8:00 am in
`16 Patients
`
`Time of Day
`
`9:00 AM 10:00 am=—s-11:00 am_~—s 12:00 Pm
`
`
`
`
`Variable
`8:00 am
`
`Systolic blood pressure, mm Hg
`
`Diastolic blood pressure, mm Hg
`
`Arterial pulse pressure, mm Hg
`
`Heart rate, bpm
`
`* P<0.01.
`
`A
`B
`
`A
`B
`
`A
`B
`
`A
`B
`
`149+5
`14944
`
`7543
`7343
`
`7444
`76+3
`
`6643
`6543
`
`13744
`149+ 4*
`7142
`7343
`67+3
`75+3*
`6543
`6243
`
`13543
`152+5*
`7042
`7443
`6543
`78+4*
`6443
`6243
`
`129+4
`145+4*
`6942
`7243
`60+3
`73+3*
`65+3
`60+3*
`
`13544
`148+ 4*
`7143
`7343
`6444
`7524"
`6543
`6343
`
`extended-release ISMN when used for angina relief was
`foundto cause tolerance if given twice daily, but not if given
`once daily (as it was in the present study).2° Tolerance
`developmentto nitrates may be minimized when co-therapy
`includes sulfhydryl agents, hydralazine, angiotensin-
`converting enzyme inhibitors, or antioxidant vitamins.!8 Four
`patients in the present study were receiving angiotensin-
`converting enzyme inhibitors and thereby could have had
`enhanced lowering of systolic blood pressure (BP) with
`ISMN.Diuretics (given to 14 patients)?! and angiotensin II
`receptor blockers (given to 8 patients) may also have en-
`hanced the effects of ISMN,22 whereas beta-blockers (given
`to 7 patients) may have diminished them.?5
`
`~+~ Sequence A
`
`--«- Sequence B
`
`“
`
`a
`
`>
`
`|
`
`
`
`AugmentationIndex(%)
`
`130-4
`
`
`
` T
`
`a
`8
`
`r
`9
`
`10
`
`T
`11
`
`T
`12
`
`T
`13
`
`ae
`14
`
`T
`15
`
`T
`16
`
`1
`17
`
`7
`
`Clocktime (hours)
`
`Figure 2, Mean values and SEM (n=16) for augmentation index
`with treatment on different study days with sequenceA (active
`ISMN at 8:05 am and placebo at 12:05 pm) and sequenceB (pla-
`cebo at 8:05 am and active ISMN at 12:05 pm). Dotted lines
`show times of ISMN/placebo administration.
`
`Page 3 of 5
`
`
`
`1707‘£1ArenigajuoAqSio‘sjeumnofeye//:dyywopopeopumog
`
`tively) and sequence B (14043 and 65+2 mm Hg); also,
`there was no order effect. Thus, the switch in active ISMN
`dosing from 8:05 Am to12:05 pm had nostatistically signifi-
`cant effect on the overall 24-hour average level of blood
`pressure (from 4:00 pm to 4:00 pm). Figure 1 showsthat both
`systolic blood pressure and diastolic blood pressure declined
`during the night and increased during the period from 5:00 AM
`to 7:00 Am. There was no appreciable hour-to-hour difference
`between sequences A and B for diastolic blood pressure
`throughout the 24-hour monitoring period, or for systolic
`blood pressure between the start and 8:00 am. However, in
`the period from 9:00 AM to 12:00 pM, systolic blood pressure
`(n=16) was lower (P<0.0001) for sequence A than for
`sequence B. Table 2 showsthat at the nadir of sequence A
`(11:00 am to 12:00 pm), the difference in mean systolic blood
`pressure between sequences was 16+4 mm Hg (P<0.001).
`Pulse pressure was also lower for sequence A, with a
`difference between sequences of 13+3 mmHgat nadir
`(P<0.001). Mean values for ambulatory diastolic blood
`pressure were not significantly different between sequences.
`Mean heart rate at nadir was 5 bpm higher for sequence A
`(P<0.01). During the period from 1:00 Pm to 4:00 pM, there
`were no differences between the sequences in mean values for
`systolic blood pressure, diastolic blood pressure, or heart rate.
`Mean values for augmentation index at 8:00 AM or 4:00 PM
`(shown in Figure 2) did not differ between sequences.
`Augmentation index at 12:00 pm was 132+4% for sequence
`A and 159+5% for sequence B; the difference was 27+4%
`(P<0.001).
`
`Discussion
`“True” biochemical tolerance to nitrates, defined as decreased
`activity of the nitric oxide-cGMPcascade,'* has long been
`recognized as a real or potential problem in treating coronary
`vascular disease. It is unknown whether tolerance can dimin-
`ish the long-term response to nitrate use for systolic hyper-
`tension. The clinical effects of tolerance are subtle and may
`be influenced by the type of nitrate used, the presence of a
`nitrate-free period in dosing schedules,!? and the co-
`administration of other therapies.'8 For example, ISMN has
`been reported to cause less tolerance development in vitro
`than either nitroglycerin or isosorbide dinitrate.19 Also,
`
`Page 3 of 5
`
`

`

`Stokes et al
`
`Long-Term ISMN in Systolic Hypertension
`
`383
`
`The present group of subjects was characterized by long-
`standing systolic hypertension refractory to conventional
`therapeutic regimens, and by increased aortic pulse wave
`reflection (before nitrate therapy). On the basis of their
`marked decreases in systolic BP and augmentation index (a
`measure of wave reflection) with acute administration of
`ISMN,!2-!> this agent had been given to them long-term. We
`have shownpreviously that during regular once-daily dosing
`with ISMN 60 to 120 mg, plasma nitrate concentration
`reached a peak level by 4 hours after dosing and declined to
`a near-zero concentration by 24 hours.!? The rationale of the
`present study was that when a placebo wassubstituted for the
`regular nitrate dose, an increase in systolic BP and augmen-
`tation index would confirm the existence of long-term re-
`sponse. For ethical reasons, the period of withdrawal of the
`active agent wasrestricted to 4 hours.
`In this selected group of patients receiving maintenance
`therapy with a regimen comprising 2 to 4 conventional
`antihypertensive agents plus extended-release ISMN,
`the
`nitrate was found to contribute at nadir a depressor effect of
`16 mm Hgin systolic BP and a decrease in pulse pressure of
`13 mm Hg. Thepossibility that these effects were distinc-
`tively nitrate-induced”* was supported by a corresponding
`pronounced effect on wave reflection, evidenced by a de-
`crease in augmentation index with active ISMN.A correction
`to the observed decrease in augmentation index is warranted
`because the accompanying change in heart rate would have
`influenced the index.?5 For a pacemaker-induced increment of
`10 bpm in heart rate, augmentation index declines by ~4%.?5
`Extrapolating this to the present study, in which heart rate at
`nadir was 5 bpm higher with active ISMN than with placebo,
`the observed ISMN-induced effect on augmentation index of
`—27+4% should be corrected to —25+4%.
`
`A limitation of these findings is that demonstration of the
`continuing effects of ISMN does not exclude the presence of
`tolerance, because the development of tolerance does not
`necessarily imply complete abolition of therapeutic effect.18
`In published acute trials, responsesto the initial dose of active
`ISMN(given at 8.00 am) versus placebo had been determined.
`for 12 of the present subjects.!2-'5 Mean values for augmen-
`tation index observed in this subgroup at nadir (12:00 pM)
`were, respectively, 123+3% and 149+4%, with no signifi-
`cant change in heart rate. Thus,
`the mean ISMN-induced
`change for augmentation index from the earlier trials was
`—26+3%. The corresponding effect for the same subgroup in
`the present study was —28+4%.
`The finding that these effects on pulse wave reflection in
`the subgroup were closely similar to each other and to the
`response for the whole study group suggests that tolerance to
`ISMNdid not develop during the long-term treatmentperiod.
`However, this evidence is not conclusive. Wave reflection
`could have been affected by changes in underlying cardio-
`vascular disease or in co-administered therapy during this
`period. This possibility is supported by a lack of significant
`correlation of the initial and long-term responses of augmen-
`tation index to ISMN within the
`subgroup subjects
`(°=0.1313; P>O.2). Thus, our finding that a distinctive
`response to ISMN persisted with long-term treatment cannot
`
`tolerance
`
`be taken to exclude the possibility of partial
`development.
`However, the important practical issue clinically is whether
`long-term ISMNuseis effective enough to warrant consid-
`eration as an antihypertensive agent in appropriately selected
`patients. The question arises as to whether the decline in
`systolic BP attributable to ISMN in this study could justify
`regular inclusion of the agent in combination therapy of
`systolic hypertension. The effects of conventional combina-
`tion therapy on systolic blood pressure in the elderly have
`been reported from controlled trials.26-29 Although significant
`therapeutic responses were shown,the average systolic blood
`pressure reached with long-term active treatment in these
`trials exceeded the currently recommended goal of
`140 mm Hg.In the Systolic Hypertension in the Elderly
`Program (SHEP), for example,
`the average value (+SD)
`reached at 5 years was 144419 mm Hg(773 patients).2” In
`the Systolic Hypertension in Europe (Syst-Eur) trial,
`the
`average systolic blood pressure at 2 years was 151 mm Hg
`(1285 patients).29 The percentages of patients failing to reach
`goal systolic blood pressure was reported as ~30% in SHEP
`and 56% in Syst-Eur. It appears from this experience that a
`strategy that decreased systolic blood pressure by a further
`16 mm Hg(equivalent to the nadir effect of extended-release
`ISMN in the present study) would have been effective in
`helping to achieve goal in thesetrials.
`Thus, extended-release nitrates have a potential adjuvant
`role in attempts to improve treatment in refractory cases of
`isolated systolic hypertension. However, we emphasize that
`our findings were restricted to patients known to be acute
`responders to ISMN, who werealready receiving a variety of
`different medications at study entry. Also,
`the high early
`morning blood pressure values observed suggest that further
`work may be required to optimize the distribution of dosing.
`
`Perspectives
`Weconclude that tolerance did not seriously diminish the
`efficacy of ISMN when used as adjuvant therapy in the
`chronic treatment of a group of patients with treatment-
`refractory systolic hypertension. The long-term antihyperten-
`sive efficacy of this agent appears to justify a trial of its use
`as an adjunct to conventional combined treatment regimens
`for the prevention of cardiovascular morbid events in patients
`with isolated systolic hypertension.
`
`References
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`therapy—a suggested new approach. J Clin Hypertens. 2004;6:192-197.
`2. Laurent S, Boutouyrie P, Benetos A. Pathophysiology of hypertension in
`the elderly. Am J Geriat Cardiol. 2002;11:34-39.
`3. Nichols WW,O’ Rourke MF, Avolio AP, Yaginuma T, Murgo JP, Pepine
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`4. Tao J, Jin Y, Yang Z, Wang L, Gao X, Liu L, Ma H. Reducedarterial
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`Henry JF, Joosens JV, Leonetti G, Lund-Johansen P, O’Malley K, Petrie
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