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208 THERAPEUTIC PRINCIPLES
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combinations of ACEis, ARBs, and direct renin inhibitor increases the risk of this side effect.
10,11
Thiazide diuretics
can cause drug interactions due to either their direct effects or as a consequence of side effects. Thiazide-induced
hypokalemia leads to digoxin toxicity by promoting increased affinity of digoxin to its receptor. Thiazides cause
lithium toxicity by promoting increase reabsorption of this drug through the renal tubules.
12,13
Finally, thiazides,
due to reasons directly related to their mechanism of action, lead to increased renal water reabsorption by way of
increased antidiuretic hormone (ADH) levels and, when coupled with selective serotonin reuptake inhibitors (SSRIs) which stimulate ADH, can cause hyponatremia.
The list of potential drug interactions is not exhaustive but a more complete list of drugs which inhibit or induce
metabolizing enzymes can be found on the Food and Drugs Administration (FDA) website.
14,15
Additional drug-drug interactions are listed in Table 39.1.
16
3. How does rifampin interact with antihypertensive mediations, and how should you alter
treatment?
Rifampin induces the expression of multiple hepatic and gastrointestinal drug-metabolizing cytochrome P450
enzymes and intestine P-glycoprotein, resulting in decreased drug concentration and half-life. Calcium channel
blockers are notably affected, although effects on multiple drugs within other classes including propranolol,
enalapril, and losartan have also been described.17 When rifampin is started, you should anticipate worsening of
hypertension if hepatically metabolized drugs are used. Alternative medications can be used, with selection of
drugs which do not have any CYP450 drug interactions. Induction of these enzymes occurs within the first 2 to
7 days and may require 2 to 4 weeks to return to baseline after stopping rifampin. Other medications such as
phenobarbital also induce multiple cytochrome P450 enzymes.
4. Are there any known genetic variants that affect antihypertensive medication effectiveness?
Although genetic variants that impact the actions of antihypertensive medications have been identified, testing for
these variants is not standard in clinical practice. These variants typically modulate drug efficacy due to mechanisms that are similar to those leading to drug-drug interactions. These mechanisms include altered drug metabolism, altered receptor affinity and alteration of the basal levels of molecular pathways that are modulated by the
antihypertensive (Table 39.3). There have been several loss of function variants within the cytochrome P450 gene
CYP2D5 that lead to increased plasma concentrations of metoprolol.
ergic receptor gene (ADRB1) decreases its affinity to beta blockers, thereby increasing dose requirements.
18–20
A missense variant in the beta-1 adren-
21,22
Multiple studies have addressed variants affecting thiazide response, and have identified several variants that
have validated across studies. A variant in the gene NEDD4L decreases basal sodium reabsorption rates in the
kidney and, in the presence of this variant, there is a relatively larger blood-pressure lowering response to thiazide
23–25
diuretics.
A missense variant in the gene NPHS1, through mechanisms that are not well-defined, and common loss-offunction variants in CYP2C9 are associated with an attenuated blood-pressure lowering response to losartan.
Variants in PRKCA, TET2, and CSMD1 have also been associated with altered thiazide response.
26–28
Table 39.3 Notable Antihypertensive Medication Drug-Gene Interactions
DRUG OR
DRUG CLASS GENE VARIANT
Metoprolol CYP2D6 (multiple decreased
Beta blocker ADRB1 (R389G) ↓Receptor sensitivity ↓Medication response
GRK4, multiple SNPs Altered receptor response ↓Medication response
Losartan NPHS1 Glu117Lys
CYP2C9, multiple variants reduced conversion to
Thiazides NEDD4L (rs4149601 G/A) Decreased sodium
PRKCA (rs16960228A) Increased PRKCA
TET2 (rs12505746) Unknown; aldosterone
CSMD1, multiple SNPs Unknown ↑Response to thiazide
SLCO2A1 (rs34550074) Reduced prostaglandin
a
BP response not consistent, compared to HR response.
DBP, Diastolic blood pressure; SBP, systolic blood pressure; SNP, single nucleotide polymorphism.
function alleles)
(rs3814995)
MECHANISM CONSEQUENCE
a
↑Plasma concentrations ↓Dose requirement
Possibly altered nephrin
function
↓SBP and DBP response to
medication
↓medication response
potent active metabolite
↑Response to thiazide with
reabsorption
A allele
↑Response to thiazide with
expression
A allele
↑Response to thiazide
responsive gene
↑Risk of thiazide-induced
E2 uptake
hyponatremia
DRUG-DRUG AND PHARMACOGENETIC INTERACTIONS 209
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5. What genetic variants alter the risk of antihypertensive medication side effects?
Genetic association studies have identified single nucleotide polymorphisms (SNPs) that associate with some
adverse drug effects. For instance, a SNP located near the gene KCNIP4 has been associated with cough due to
ACEis.29 A genetic variant in SLCO2A1 which reduces the uptake of prostaglandin E2 is associated with increased
risk of thiazide-induced hyponatremia.30 As genetic testing and documentation of side effects improves, more
associations are likely to emerge which provide insight into side effect mechanisms. However, to date, there have
been no genetic variants of clinical significance that are associated with medications side effects, and routine
genetic testing is not currently indicated.
6. Are there any genetic variants that should be tested for prior to starting an antihypertensive
medication?
In clinical practice, antihypertensive medications are titrated until blood pressure targets are realized. The magnitude of the blood pressure modulating effects of the genetic variants identified to date are too small either to
enhance dose titration or to result in significant harm. Thus, genetic testing is not recommended prior to initiating
antihypertensive therapy.
KEY POINTS
1. Drugs may counteract the effectiveness of antihypertensive medications by altering drug metabolism or
counteracting the targeted blood pressure-lowering mechanisms.
2. Adverse drug interactions with antihypertensives can be due to overlapping mechanisms of action or
exaggerated shared side effect profiles.
3. Common genetic variants which alter the effectiveness or increase the risk of adverse reactions to
antihypertensives have been identified.
4. Testing for genetic variants is not recommended before initiating or altering the doses of antihypertensive
medications.
RefeRences
1. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–2221.
2. Cordeanu EM, Gaertner S, Faller A, et al. Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension.
Fundam Clin Pharmacol. 2017;31:587–589.
3. Tada Y, Tsuda Y, Otsuka T, et al. Case report: nifedipine-rifampicin interaction attenuates the effect on blood pressure in a patient
with essential hypertension. Am J Med Sci. 1992;303:25–27.
4. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin, clinical relevance. Clin
Pharmacokinet. 2003;42:819–850.
5. Xu Y, Zhou Y, Hayashi M, Shou M, Skiles GL. Simulation of clinical drug-drug interactions from hepatocyte CYP3A4 induction data and
its potential utility in trial designs. Drug Metab Dispos. 2011;39:1139–1148.
6. Agrawal A, Agarwal SK, Kaleekal T, Gupta YK. Rifampicin and anti-hypertensive drugs in chronic kidney disease: pharmacokinetic
interactions and their clinical impact. Indian J Nephrol. 2016;26:322–328.
7. Webster J. Interactions of NSAIDs with diuretics and beta-blockers mechanisms and clinical implications. Drugs. 1985;30:32–41.
8. Koopmans PP, Kateman WG, Tan Y, van Ginneken CA, Gribnau FW. Effects of indomethacin and sulindac on hydrochlorothiazide
kinetics. Clin Pharmacol Ther. 1985;37:625–628.
9. Houston MC. Nonsteroidal anti-inflammatory drugs and antihypertensives. Am J Med. 1991;90:42S–47S.
10. Parving HH, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–2213.
11. Zheng SL, Roddick AJ, Ayis S. Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes
and cardiovascular disease or risk: a systematic review and meta-analysis of 13,395 patients. Diab Vasc Dis Res. 2017;14:400–406.
12. Petersen V, Hvidt S, Thomsen K, Schou M. Effect of prolonged thiazide treatment on renal lithium clearance. Br Med J.
1974;3:143–145.
13. Thomsen K, Schou M. The effect of prolonged administration of hydrochlorothiazide on the renal lithium clearance and the urine
flow of ordinary rats and rats with diabetes insipidus. Pharmakopsychiatr Neuropsychopharmakol. 1973;6:264–269.
14. Rosner MH. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors.
Am J Med. Sci. 2004;327:109–111.
15. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother.
2006;40:1618–1622.
16. Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. FDA https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers (2020).
17. Holtbecker N. Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The nifedipine-rifampin interaction. Evidence for induction of gut
wall metabolism. Drug Metab Dispos. 1996;24:1121–1123.
18. Metoprolol therapy and CYP2D6 genotype. In: Dean L, Pratt V, eds. Medical Genetics Summaries. National Center for Biotechnology
Information (US); 2012.
19. Hamadeh IS, et al. Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate. Clin Pharmacol Ther.
2014;96:175–181.
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20. Bijl MJ, et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users.
Clin Pharmacol Ther. 2009;85:45–50.
21. Pacanowski MA, et al. beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin
Pharmacol Ther. 2008;84:715–721.
22. Sandilands A, Yeo G, Brown MJ, O’Shaughnessy KM. Functional responses of human beta1 adrenoceptors with defined haplotypes
for the common 389R > G and 49S > G polymorphisms. Pharmacogenetics. 2004;14:343–349.
23. Luo F, et al. A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension.
Hypertension. 2009;54:796–801.
24. Manunta P, et al. Physiological interaction between alpha-adducin and WNK1-NEDD4L pathways on sodium-related blood pressure
regulation. Hypertension. 2008;52:366–372.
25. McDonough CW, et al. Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in
hypertensive patients treated with thiazide diuretics. J Hypertens. 2013;31:698–704.
26. Hiltunen TP, et al. Pharmacogenomics of hypertension: a genome-wide, placebo-controlled cross-over study, using four classes of
antihypertensive drugs. J Am Heart Assoc. 2015;4:e001521.
27. Rimpelä JM, et al. Replicated evidence for aminoacylase 3 and nephrin gene variations to predict antihypertensive drug responses.
Pharmacogenomics. 2017;18:445–458.
28. Eadon MT, Maddatu J, Moe SM, Sinha AD, Melo Ferreira R, Miller BW, Sher SJ, Su J, Pratt VM, Chapman AB, Skaar TS, Moorthi
RN. Pharmacogenomics of hypertension in chronic kidney disease: the CKD-PGX study. Kidney360. 2021;doi: 10.34067/
kid.0005362021:10.34067/KID.0005362021.
29. Mosley JD, et al. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.
Pharmacogenomics J. 2016;16:231–237.
30. Ware JS, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. J Clin Invest.
2017;127:3367–3374.
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Swapnil Hiremath, MD
QUESTIONS
1. What do we mean by device therapies in hypertension?
Device therapies refers to interventions that are used to reduce blood pressure (BP). These interventions can be
surgical, or with interventional angiographic procedures targeting the mechanism of hypertension. The device
therapies that have undergone research in this area include
• Renaldenervation
• Baroreceptoractivationormodulation
• Centralarteriovenousstula(AVF)creation
A brief summary of the effect of these interventions and their current status is presented in Table 40.1.
Renal Denervation:
Catheter based radiofrequency (Simplicity and Spyral catheters, Medtronic Inc, Dublin, Ireland; EnligHTN system,
St Jude Medical Inc, St Paul, MN)
Catheter based ultrasound (Paradise system, ReCor Medical, Palo Alto, CA)
Catheter based alcohol (Peregrin system, Ablative Solutions, Wakefield, MA)
Baroreceptor:
Baroreceptor activation: Bilateral multielectrode system (Rheos) and unilateral (CVRx Inc, Minneapolis, MN)
Baroreceptor modulation: MobiusHD system (Vascular dynamics Inc, Mountain View, CA)
Central Arteriovenous Fistula: ROX coupler (ROX Medical, San Clemente, CA)
2. What is the history of interventions for hypertension?
In 1923, Bruning had suggested sympathectomy for control of hypertension as the role of the efferent sympathetic
system in maintaining BP had already been discovered then. A few years later, following the observation that
sympathectomy, performed for peripheral arterial disease, results in prolonged vasodilation, Adson and Brown
performed the section of the nerve roots from D6 to L2 and noted a dramatic decrease in BP from 250/180 to
170/120.1 Over the next few years, this procedure was used in severe cases of hypertension, but it was quickly
noted that the impressive BP drop was accompanied by impressive adverse effects, such as loss of sensation,
CHAPTER 40
Table 40.1 Summary of Device Therapies, Effect on BP, Adverse Effects, and Current Status
INTERVENTION EFFECT ON BP POSSIBLE ADVERSE
Lumbar sympathectomy ∼ 70 mm Hg decrease Paralytic ileus, impotence,
Renal denervation Initial reports
Baroreceptor ∼ 16 mm Hg decrease
Central arteriovenous
fistula
ABPM, Ambulatory blood pressure monitoring; B P, blood pressure; RCT, randomized controlled trial.
20–30 mm Hg
Sham controlled
decrease in ABPM ∼
4/2 mm Hg
inofceBPcompared
to 9 mm Hg in control
group in pivotal RCT
∼ 13 mm Hg decrease
in ABPM
EFFECTS
loss of sweating,
sensation, death
Low risk of procedural
complications
Potential risk of shock
with hypovolemia or
hemorrhage
∼ 4%–5 % developed
facial nerve injury or
damage with initial
device
Dysphagia, paresthesia
30% risk of procedural
complications and
venous stenosis (early)
Potential late complications
include heart failure
CURRENT STATUS
Abandoned
Approved in Europe
and some other
countries
Not approved in North
America as of 2021
Approved in Europe
Barostim Neo being
pursued for heart
failure
MobiusHD in pilot trials
Abandoned
211
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paralytic ileus, problems with ejaculation, loss of sweating, and the occasional mortality. Once effective pharmacological therapy became available, this procedure fell into disfavor and was abandoned.
3. How does renal denervation work?
Renal denervation was rejuvenated by clinical research that demonstrated the role of afferent nerves from the
kidney which increase the efferent sympathetic tone. Using catheter-based radiofrequency ablation, it was found
that targeting the nerves in the renal artery resulted in a BP decrease. The BP decrease was initially reported to be
intheinitialcasereport,andinthersttwoclinicaltrials,whichwereperformedinpatientswithsevere,resistant
hypertension.
4. What is the current evaluation of the effect of renal denervation?
The initial bubbling enthusiasm in renal denervation defervesced after the reporting of the SYMPLICITY HTN-3
trial.4Thiswastherstshamcontrolledrandomizedclinicaltrial(RCT),whichalsoused24-hourambulatory
blood pressure monitoring (ABPM) as the outcome. Though there was a decrease in BP from baseline with renal
denervation, this was no different than the change in BP in the control group. Subsequent analysis suggested
that the cause of this discrepancy may have been related to the expertise in denervation, and varying adherence.
Subsequent trials were designed to overcome these potential flaws by using a multielectrode catheter, or an ultrasound-based denervation procedure. They also enrolled participants with mild hypertension (on no medications)
or on less than three medications who underwent direct observed therapy before measurement of ABPM. These
subsequent trials have demonstrated a reduction in ABPM of about 4/2 mm Hg compared to sham control.
5. What are the possible advantages of renal denervation over medications?
The proponents of renal denervation point to a few potential advantages of renal denervation. Firstly, with the
procedural effect of BP lowering, the variable effect of adherence, or lack thereof, is eliminated. Secondly, denervation may provide a smoother decrease in BP compared to the peaks and troughs seen with pharmacological BP
lowering (Fig. 40.1).
6. What about long-term efficacy and effect on clinical outcomes?
The clinical trials reported do not extend beyond 6 months. There is concern that the ablated nerves could possibly regrow, and the BP lowering effect may be attenuated. The Global SYMPLICITY Registry does not report this;
however, it is a registry and not a clinical trial. The existing RCTs have not been powered for clinical outcomes.
Unfortunately, in the setting of resistant hypertension, the incidence of adverse cardiovascular outcomes is high,
however, the variance is also high, so a properly powered RCT will be prohibitively infeasible.
2,3
4–8
Fig. 40.1 24 Hourly ambulatory systolic blood pressure and diastolic blood pressure at baseline and 6 months, according to patientrecorded individual wake times. RDN, Renal denervation. (From Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on
bloodpressureinthepresenceofantihypertensivedrugs:6-monthefcacyandsafetyresultsfromtheSPYRALHTN-ONMEDproof-of-
concept randomised trial. Lancet. 2018;391(10137):2352)
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7. What are the potential safety issues or disadvantages of renal denervation?
In the RCTs, there was a low risk of procedural complications, such as the risks associated with femoral puncture,
and rare cases of arterial trauma. There is concern about the long-term effect of renal sympathetic denervation
in the setting of hypovolemic shock, when the counterregulatory effect of an activated sympathetic system might
be essential. In animal (sheep) studies, renal denervation and subsequent hemorrhage has been demonstrated to
result in severe shock. A similar case report in a patient has also been reported in a patient with sepsis. However,
these effects are still thought to be uncommon or rare. The risk of adverse outcomes in the global SYMPLICITY
registry is low, providing a modicum of reassurance.
8. Why was there a discrepancy between early studies and later?
The initial studies with renal denervation suggested that the effect of this procedure might be as much as a
decreaseinsystolicBPof20to30mmHg.Thishopewasbelied,andthenaleffectseemstobeabout4/2mm
Hg. This effect is similar to the effect of a single BP lowering medication.
An elegant analysis explores the various causes for the difference.9 The initial uncontrolled trial may reflect
regression to mean, due to selection of patients with very high BP, which would be expected to be lower at the
next measurement, irrespective of any action or intervention. In the controlled trials which were not blinded,
observer bias during measurement of BP, and participant bias on change in adherence to BP lowering medications, may cause an inflation in the observed effect. Hence the subsequent trials were performed in a population
nottakingBPmedications,orwithholdingmedicationforthetrialperiod,orifonBPmedicationsbyconrming
adherence the best way you can during the trial. One can see the effect of the major trials in Table 40.2. Note that
inSYMPLICITYHTN-3,therewasasignicantloweringofBPintheshamarm(about12/5mmHg)withnochange
in medications, which might reflect greater adherence in patients who believed they had the procedure.
9. Who should have renal denervation?
Renal denervation has, at the time of this writing, not yet been approved in North America, though it has been
approved and has been in use in Europe and other jurisdictions. Paradoxically, though one might expect that the
role of renal denervation would be in patients with resistant hypertension, or even refractory hypertension (i.e.,
afteradditionofamineralocorticoidantagonistasthefourthagent),fewtrialshavereportedtheefcacyofrenal
Table 40.2 Major Sham Controlled Randomized Trials of Renal Denervation
Denervation
method
SYMPLICITY 3
Simplicity
(single
electrode)
Main renal
artery
SPYRAL ON
PILOT
Simplicity G-3
or SPYRAL
(multi-
electrode)
Main + branch,
RADIANCE
TRIO
Paradise system
(ultrasound)
Main renal ar-
tery, 2 spots
5 mm apart
SPYRAL
OFF
PIVOTAL
Simplicity G-3
(multi-
Main + branch,
accessory
>3 mm
Other features − Direct observed
therapy
before ABPM
pre/post
On medications;
single pill
combination
of 3 drugs
Off medica-
Drug levels
Drug levels
measured
Follow up
6 months 6 months 2 months 3 months 2 months
measurement
Change in
−14.1/−6.75 −9.0/−6.0 −8.0/−4.9 −4.7/−3.7 −7.0/−4.4
24-hour ABPM
in Denervation
Change in
−11.7/−4.8 −1.6/−1.9 −3.0/−2.0 −0.6/−0.8 −3.1/−3.0
24-hour
ABPM in Sham
Difference in the
−2.4/−1.96 −7.4/−4.1 −4.5/−1.8 −3.9/−2.9 −4.1/−1.8
arms
ABPM, Ambulatory blood pressure monitoring.
or SPYRAL
electrode)
accessory
>3 mm
tions
measured
RADIANCE
SOLO
Paradise
system
(ultrasound)
Main renal
artery,
2 spots
5 mm
apart
Off medica-
tions
214 THERAPEUTIC PRINCIPLES
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denervation in this setting. Nevertheless, the case might be made that an additional effect may be obtained in
these patients, who are at an otherwise higher risk of adverse outcomes from the consequence of uncontrolled
hypertension. In addition, a case has also been made for the use of renal denervation in patients who are not
adherent or are intolerant of BP lowering medications.
10. What is the evidence in baroreceptor stimulation or modulation?
Baroreceptor activation therapy (BAT, Rheos system, CVRx Inc, Minneapolis, MN) relies on the activation of the
myogenic stretch reflex in the carotid body, which would reduce central sympathetic activity and lower BP. The
initial system consisted of multiple electrodes placed around both carotid sinuses, connected to a subcutaneous
pulse generator, which could be switched on or off. After the initial promising pilot RCT data, the pivotal double
blindRheosRCTdidnotdemonstrateasignicantBPloweringwithBATcomparedtosham.10 The proportion
of responders in the group in whom the device was activated was 54% compared to 46% in the control arm
(P =.97).ThedecreaseinofcesystolicBPwas16±29mmHgfortheactivegroupand9±29mmHgforthe
control (P = .08). More importantly, 25% of participants developed procedural adverse events. Subsequently,
a second-generation device (Barostim Neo) has been developed which has a single disc electrode, is inserted
unilaterallywithapotentiallysafersafetyprole,andisundergoingongoingtrials,thoughfocusedonheartfailure.
Another endovascularly delivered implant device, Mobius HD (Vascular dynamics Inc, Mountain View, CA), which
increases wall strain in the carotid sinus, thus more of a baroreceptor modulator than activation, has similarly
shown promise in a single arm pilot RCT (lowering of ABPM by ∼21 mm Hg) and is undergoing a larger double
blind RCT (CALM-2, NCT03179800).
11. What is the role of a central arteriovenous fistula in controlling hypertension?
Creation of an AVF adds a low-resistance, high-compliance venous segment to the central arterial tree to potentially exploit the natural mechanical effects and lower BP. A high output AVF in other settings (trauma, and dialysis)
has been known to have hemodynamic effects. An RCT of a device (ROX coupler, ROX Medical, San Clemente,
CA)whichcreatedaniliacAVFreportedadecreaseinofcesystolicBPof27mmHgandABPMof13mmHg.11
However, more than 50% of participants had procedural complications, and 30% developed venous stenosis
requiring intervention during follow-up. In addition, high output heart failure is a known complication of AVF from
other settings.12 Unsurprisingly, further development of this intervention has been wisely abandoned.
12. What are the other device therapy options that have been tried?
Afewotherinterventionshavebeenattemptedovertheyears,butrobustdenitivedataarestillawaitedtoshow
that these reliably decrease BP. These include median nerve stimulation, device guided breathing, and a microvascular decompression surgery for refractory hypertension of possible neurogenic etiology.
KEY POINTS
1. Device therapy in the modern era refers to denervation of renal sympathetic afferent nerves, activation or
modulationofthebaroreceptors,andcentralarteriovenousstulacreation.Wehavemostdatasupportinga
blood pressure lowering effect with renal denervation.
2. Despite initial reports of huge blood pressure decrease from uncontrolled and unblinded studies, properly
conducted trials demonstrate a more modest 4 to 7 mm Hg decrease with renal denervation, approximately the
effect seen with the addition of one blood pressure lowering drug.
3. Design issues such as blinding to avoid varying adherence and measurement bias, sham procedures to enforce
blinding, monitoring adherence, and measurement of blood pressure with ambulatory monitoring are essential to
provide robust results in device therapy trials.
4.Centralarteriovenousstulamaylowerbloodpressure,butwithhighcomplicationrates,andshouldnotbe
pursued at this time.
5. Baroreceptor modulation/activation seems to have interesting physiologic effects, however, data from ongoing
trialsonsafetyandefcacyareneededbeforewidespreaduse.
RefeRences
1. AdsonAW,BrownGE.Malignanthypertension:reportofcasetreatedbybilateralsectionofanteriorspinalnerverootsfromthesixth
thoracic to the second lumbar, inclusive. JAMA. 1934;102(14):1115–1118.
2. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The
SYMPLICITY HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903–1909. https://doi.org/10.1016/S0140-
6736(10)62039-9.
3. Schlaich MP, Sobotka PA, Krum H, et al. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med.
2009;361(9):932–934. https://doi.org/10.1056/NEJMc0904179.
ROLE OF DEVICE THERAPY 215
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4. BhattDL,KandzariDE,O’NeillWW,etal.Acontrolledtrialofrenaldenervationforresistanthypertension.N Engl J Med.
2014;370(15):1393–1401. https://doi.org/10.1056/NEJMoa1402670.
5. Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive
drugs:6-monthefcacyandsafetyresultsfromtheSPYRALHTN-ONMEDproof-of-conceptrandomisedtrial.Lancet.
2018;391(10137):2346–2355. https://doi.org/10.1016/S0140-6736(18)30951-6.
6. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO):
a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018;391(10137):2335–2345. https://doi.
org/10.1016/S0140-6736(18)31082-1.
7. BöhmM,KarioK,KandzariDE,etal.Efcacyofcatheter-basedrenaldenervationintheabsenceofantihypertensivemedications
(SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet. 2020;395(10234):1444–1451. https://doi.
org/10.1016/S0140-6736(20):30554-7.
8. Azizi M, Sanghvi K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill
(RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial [Published online May 16, 2021]. Lancet.
2021;397(10293):2476–2486. https://doi.org/10.1016/S0140-6736(21)00788-1.
9. Howard JP, Shun-Shin MJ, Hartley A, et al. Quantifying the 3 biases that lead to unintentional overestimation of the blood
pressure-lowering effect of renal denervation. Circ Cardiovasc Qual Outcomes. 2016;9(1):14–22. https://doi.org/10.1161/
CIRCOUTCOMES.115.002533.
10. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension:
results from the double-blind, randomized, placebo-controlled Rheos pivotal trial. J Am Coll Cardiol. 2011;58(7):765–773. https://
doi.org/10.1016/j.jacc.2011.06.008.
11. Lobo MD, Ott C, Sobotka PA, et al. Central iliac arteriovenous anastomosis for uncontrolled hypertension: one-year results from the
ROX CONTROL HTN trial. Hypertension. 2017;70(6):1099–1105.
12. MacRae JM, Dipchand C, Oliver M, et al. Arteriovenous access: infection, neuropathy, and other complications. Can J Kidney Health
Dis. January 2016;. https://doi.org/10.1177/2054358116669127.
6 Miscellenia
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ORTHOSTATIC HYPOTENSION
Maureen C. Farrell, MS, and Cyndya A. Shibao, MD MSCI
CHAPTER 41
QUESTIONS
1. What physiologic responses prevent blood pressure from decreasing acutely when we
stand?
After assuming the upright position, gravitational forces shift ∼700 mL of blood volume to the lower part of
the body, mostly in the splanchnic vascular circulation. This fluid shift is detected by the baroreceptors in the
carotid sinus and aortic arch This information is transmitted through the glossopharyngeal and vagus nerves to
the nucleus tractus solitarii (NTS) in the medulla oblongata. These neurochemical stimuli trigger changes within
the hypothalamus that upregulate sympathetic activity and downregulate parasympathetic activity of the heart.
Subsequently, the heart rate (HR) increases and the vasculature in the peripheral and splanchnic beds constrict to
maintain the cardiac output and prevent a decrease in blood pressure. In addition to the autonomic response, the
renin-angiotensin-aldosterone system (RAAS) becomes activated, generating angiotensin II as a potent vasoconstrictor. The RAAS response time is delayed compared to sympathetic nervous system activation.
2. What is orthostatic hypotension?
Orthostatic hypotension (OH) describes a sustained reduction in systolic blood pressure of at least 20 mm Hg or
diastolic blood pressure of 10 mm Hg within 3 minutes of standing or head-up tilt to at least 60 degrees on a tilt
table.1 Such drops in blood pressure often cause dizziness, blurry or tunnel vision, fatigue, dull neck and shoulder
pain, and increased fall risk. Symptoms improve when seated or in recumbent position. Importantly, OH is associated with reduced functional capacity and mortality in elderly patients (Fig. 41.1).
2
Fig. 41.1 Tilt table testing consists of continuous heart rate and blood pressure measurements during 60-degree tilt on an adjustable
table. In patients with autonomic failure, blood pressure does not respond to increases in heart rate during tilt. Orthostatic symptoms result.
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3. How should blood pressure be measured to diagnose OH?
The most sensitive and precise measurements should be obtained during fasting conditions, early in the morning.
Blood pressure and HR measurements should be taken after the patient has been lying supine for at least 5 minutes and twice more after standing at 1 and 3 minutes. If time precludes the acquisition of orthostatic vital signs,
blood pressure and HR can be measured in the seated position and after standing.3 However, these measurements
have low sensitivity to detect OH. Concomitant HR changes on standing provide additional information on the
cardiovascular autonomic reflexes. Elevations in HR below 10 bpm during OH episodes should raise high suspicion
for an autonomic neuropathy, and autonomic testing may be warranted.
4. Describe the most common causes of OH.
The most common cause of OH is polypharmacy. Medications, including alpha-1 blockers such as terazosin, prazosin, and tamsulosin, can predispose the patient to developing OH. In addition, tricyclic antidepressants, overuse
of diuretics, and tizanidine (muscle relaxant) can also induce OH.4 Transient conditions such as dehydration (poor
oral intake, vomiting, diarrhea, or blood loss) may also cause OH and are often accompanied by significant orthostatic tachycardia. Less common causes of OH include primary autonomic neuropathies such as pure autonomic
failure, multiple system atrophy (MSA), and Parkinson disease.5 Secondary causes of autonomic neuropathies are
diabetes mellitus, amyloidosis and autoimmune autonomic failure, and paraneoplastic syndromes.
5. How should a differential diagnosis be established for orthostatic hypotension in a hypertensive patient?
Although the definition of OH indicates a drop in systolic blood pressure of >20 mm Hg, for hypertensive patients,
reduction of >30 mm Hg is required to be considered OH.1 In hypertensive patients, the differential diagnosis
includes the following etiologies:
• Neurogenic orthostatic hypotension with supine hypertension (HTN): patients with this condition have
significant OH with a decrease in blood pressure of 60 to 70 mm Hg and evidence of autonomic neuropathy
with abnormal autonomic function. About 50% of these patients develop supine HTN defined as a sustained
nocturnal systolic blood pressure above 150 mm Hg.6 Consider ambulatory blood pressure monitoring to detect
supine HTN at night.
• Baroreflex failure: Suspect baroreflex failure in patients with a history of head or neck radiation, which may
have occurred over 10 years prior to the development of OH.7 You must also inquire about past surgical history,
especially for neck surgery for carotid tumor excision or stenting for significant carotid artery atherosclerosis
as they are iatrogenic causes of OH. Hypertensive episodes can be triggered by pain, stress, or other stimuli
including exposure to light or cold. They resolve with sympatholytic agents such as oral clonidine at bedtime
or as needed. Long-acting antihypertensive agents are not recommended in patients with baroreflex failure as
they worsen OH.
• Pheochromocytoma: these patients present with episodes of HTN and diaphoresis alternating with episodes
of OH due to volume contraction caused by pressure natriuresis.9 The suggested screening and initial evaluation in patients with suspected pheochromocytoma is detailed in Chapter 10 Pheochromocytoma, typically
starting with fractionated metanephrines in either the plasma or the urine. The evaluation of patients with
positive confirmatory testing should include an adrenal computed tomography scan with and without contrast
to localize the adrenal pheochromocytoma. In certain cases, positron emission tomography (PET) imaging is
required to localize extraadrenal tumors.
• Other causes: alpha-2 agonist medications such as tizanidine or clonidine can cause rebound HTN and OH
when taking supratherapeutic doses Chapter 38.4 Plasma catecholamines are markedly elevated during the
withdrawal period, but suppressed if measured during drug administration.
8
6. Which patients are most likely to develop neurogenic OH?
Neurogenic OH is most common in adults over 75 years old and is responsible for 233 hospitalizations out of every 100,000 annually.10 Several physiological changes occur with aging that predispose older patients to develop
OH:
• thebaroreceptorsbecomelesssensitiveindetectingbloodpressureuctuations.
• alpha-1mediatedvasoconstrictionresponseisdiminished.
• thekidneyhasreducedcapacitytoconcentrateurine.
• theagingheartbecomesstiffandlesscomplianttoaccommodatelargebloodvolumesandincreasedcardiac
output.
In addition to advanced age, movement disorders like Parkinson disease are associated with the develop-
ment of OH due to autonomic failure.
7. What are the best clinical assessments for accurately diagnosing neurogenic OH?
Orthostatic vital signs should be performed in all patient with suspicious of autonomic neuropathy. Autonomic
function testing can be used to diagnose neurogenic OH (nOH); these tests are usually performed in specialized
clinical centers. However, the ratio of increase in HR to decrease in systolic blood pressure (∆HR/∆BP) provides
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