The Treatment of Resistant Hypertension (a practical guide)

Dr Andrew SP Sharp, MBChB, MD, FRCP

Consultant Cardiologist and Honorary Senior Lecturer

Royal Devon and Exeter Hospital and University of Exeter

HT - most frequently managed problem in primary care

What is ‘resistant’ hypertension?

• Definition: BP>140/90 despite three anti-hypertensive agents, typically including a diuretic

• Clearly some groups (diabetes, CKD) may have a stricter target of SBP 130mmHg

• The SPRINT study has posed the question of an even lower potential threshold of SBP 120mmHg

• Proportion reaching systolic target of 140 in the UK (and globally) varies between 50 and 75% at best

Why is Hypertension important?

• Responsible for up to half of all cardiovascular events

• Affects 1 billion people worldwide

• Expected to rise to 1.5 billion in 2025

• Half over people over the age of 60 in the UK have HT (140/90)

BP relationship with outcomes

• It is a relatively linear relationship between BP and outcomes

• Above 115/70, each rise in BP of 20/10 doubles rate of stroke and MI

Lewington et al. 2002. Lancet.

BP relationship with outcomes

• MI is similar relationship

• 2mmHg rise = 10% increased risk of stroke

• 2mmHg rise = 7% increased risk of MI

Lewington et al. 2002. Lancet.

So how are we supposed to treat HT?

• Confirm HT

• Lifestyle adaptations

• Drug treatments

• (Experimental treatments)

• Avoiding pills can be a powerful motivator for some patients

• Much harder to transform lifestyle than take pills

• But… when offered the possibility of stopping pills once they’ve started taking them….

NICE CG127

What is the magnitude of lifestyle interventions in HT?

Lifestyle factors

• Unfortunately, individual targeting of a risk factor leads to bigger effects than summative targeting

• This shows how when targeting several factors, the overall effect is less than the sum of the parts

• Still worth having – the equivalent of 1-2 drugs for the remainder of the patient’s life

• Hence, if a patient genuinely has a BP of >160, they are very likely to need drugs to reach 140/90

NICE CG127

Drug treatment - conventional

• In the elderly, a diuretic may be more effective at an earlier stage

• Following PATHWAY study, fourth line agent should now be spironolactone

• May not be more effective earlier in pathway, so stick to fourth line

PATHWAY-2

• Randomised patients to spiro, doxazosin, bisoprolol or placebo as fourth line drug

• Spironolactone had double SBP efficacy than either of other drugs

• Consistent effect across the cohort

Williams et al. Lancet, 2015

SPRINT study • SPRINT re-affirmed what we have known

for a very long time • The lower the BP the better for most

patients in terms of cv risk • Target of 140 vs target of 120 (achieved BPs

were 136 and 121) in patients with one CV risk factor

• At 3 years, all-cause mortality was 27% lower

• Actual reduction – 1.65 vs 2.2% per year • Treat 200 people for 3 years to prevent

three hard events • Clearly, we wish to avoid S/E whilst doing

so

Primary endpoint: Death from CV cause, ACS, Stroke, HF. NEJM 2015

What do we do with SPRINT

Tackling ‘resistant’ hypertension

BP persistently well above target

BP persistently well above target

Drug resistant

Not taking drugs White-coat HT

Undiagnosed secondary cause

White Coat Hypertension

• Office Blood Pressure >20/10 greater than daytime average BP on ABPM

• CV Risk appears to be closer to that of normotension than that or true hypertension

• Most hypertensives have some degree of office elevation

• This is why we add 5-10mmHg to ABPM to estimate office pressure

White Coat hypertension

• Confirm BP is persistently raised

– Home BP monitoring

– ABPM

• Association with ‘anxiety status’ not as clear cut as one might think

• If home BP and/or ABP is <135/85, we do not treat office numbers, even if they appear consistently high

Are they taking their drugs?

69.7

5.5 3.1 4.1

2.2 2.5 0.5

3.7 0.5

8.2

0.00 1.00 2.00 4.35 13.04 26.09 39.13 52.18 78.27 104.36

People (%)

Number of Weeks Willing to Trade

Hutchins et al. Circ Cardiovasc Qual Outcomes. 2015;8:00-00. DOI: 10.1161/CIRCOUTCOMES.114.001240.

8% of Adults Would Rather die two years early than take drugs forever

Improving Compliance

• If your patients is on a lot of drugs (>6) and BP is still high, the most likely explanation is non-compliance

• Over half of all patients do not take all their tablets regularly

• What can we do to improve matters?

• It is a rather prosaic process…

Improving compliance

Education

– Continually re-iterate that each 2 point drop equals 10% drop in stroke risk

– Event curves seem to be quite effective

– Continually re-iterating at each BP check that regular use = optimal effect

Improving compliance

Eliminate side effects at the first hint of presence

• I directly ask about each of the three most common side effects at first follow-up after starting drug

• If the patient hints at a problem, their compliance rates will be much lower than they will admit to

• I switch them out if there is even a hint and they are willing to change

Improving compliance - CCBs • Amlodipine causes more ankle swelling (and

other SE) than lercanidipine

• Ankle swelling is caused by decrease in arteriolar resistance that is not mimicked in veins

• Less likely if ACE started before a CCB

• Amlodipine 10mg has much higher rates of AE, with additional efficacy that can be achieved in other ways

• If a patient worries about ‘lots of tablets’ I might use 10mg dose once four drugs are maxed out

Improving compliance - Diuretics

• Telling patients they don’t have to take diuretics every day and at the same time seems to improve compliance

• Avoiding getting ‘caught short’ important factor in keeping the patients on treatment

• Can take their diuretics at differing times to suit social life

Improving compliance – ACE-I

• At first BP contact after instigation of treatment, a direct question on ‘tickly cough’

• Switch out to ARB if a hint of cough and tell them it won’t come back

• Accept up to 30% rise in creatinine in pts without advanced CKD

Improving compliance - Spironolactone

• Gynaecomastia will usually lead to non-compliance in men

• Best to ask directly and switch out to (>50% reduced efficacy) eplerenone if they have had a BP response

• Rate of gynaecomastia in males in ASCOT was 6%

Improving compliance – B- Blockers • Where do we start?

• A direct question on impotence in men

• Vasodilating B-Blockers have fewer side effects (Carvedilol, Nebivolol)

• Recent study has questioned whether central aortic pressure really is preferentially lowered by the newer B-Blockers vs old

• We know from the CAFÉ study that amlodipine +/- ACE lowers central pressure more than BB +/- thiazide

Combination pills

• Adding a second drug is typically more effective than doubling the dose of the first first drug

• Wald et al suggest up to 5 times more effective

• However, that creates problems of polypharmacy

• 80% of efficacy from ‘half-dose’ but far fewer S/E

We are at four for the price of one now…

Lancet Feb 2017

Quad pill

• Four quarter doses

– Irbesartan 37.5

– Amlod 1.25

– HCTZ 6.25

– Atenolol 12.5

• 18 patient study

• ABP reduction of 19mmhg

Compliance testing

• I do this on all resistant hypertension patients who

– Do not respond to conventional measures

– Are being consider for experimental treatments

• That means directly observed therapy with an ABPM on or urine testing

Compliance testing

• ABP results after 24 hours are frequently lower than expected

• Some drop from SBP 200 to 120 by time they go to bed

• A few patients require IV fluids

• Alternative strategy is urine drug testing

• Cheap - £30 a go (compared to 30 years of prescriptions that end up in a cupboard)

Undiagnosed secondary cause

Secondary causes

• Most organisations say look for a secondary cause when age is <40 or when a fourth drug is required

• There is a list of things to look for with potentially important confounders for many of the investigations

Secondary causes

Common

• Hyperaldosteronism (Conn’s)

• Renal parenchymal disease

• Renal Artery disease

• Obstructive Sleep Apnoea

• Drugs (esp NSAIDs)

Less common

• Cushing’s

• Phaeochromocytoma

• Thyroid/Parathyroid disease

• Acromegaly

• Coarctation

Conn’s

• Aldosterone excess from adrenal adenoma or hyperplasia

• Many (but not all) will exhibit abnormal potassium handling

– Low K at diagnosis of HT

– Abnormally low K despite ACE/ARB

• Spectacular response to spironolactone

• Published datasets suggest that in the ‘resistant’ group, may be up to 12% of cases

• Audit of my hypertension clinic more like 3%

Testing for Conn’s

• Most drugs will affect the results, either by increasing or decreasing the Aldosterone/renin ratio

• If possible, remove all anti-hypertensive agents

• If severity of HT is a concern: – Verapamil MR

– Doxazosin

– Hydralazine

• Next steps include saline suppression testing, adrenal vein sampling

• Even fine cut CT can miss adenomas that might be potentially treatable

• If a patient would not consider surgery and spironolactone controls BP…..

OSA

• Is a contributor to resistant hypertension

• However, despite evidence of BP response to CPAP (up to 6mmHg in RHT) no signal of improvement in CV outcomes

• Best BP treatment is to address the underlying issues (obesity, alcohol etc)

• May need CPAP to do this

Renal issues

• Renal arterial disease on CTCA or MRA

– Atherosclerosis

– FMD (typically younger patients)

Drugs

• Widespread availability of NSAIDs is such that frequently missed drivers of HT

• Variable impact on individuals 3-15mmHg according to baseline BP, other drugs, age, co-morbidities

• Patients have made it to my hypertension clinic through several different doctors and only then admit to taking >3g/day of ibuprofen OTC

‘Genuine’ drug resistance

Drug treatment - conventional

• In the elderly, a diuretic may be more effective at an earlier stage

• Following PATHWAY-2 study, fourth line agent should now be spironolactone

• May not be more effective earlier in pathway, so I suggest sticking to fourth line

PATHWAY-2

• Randomised patients to spiro, doxazosin, bisoprolol or placebo as fourth line drug

• Spironolactone had double SBP efficacy than either of other drugs

Williams et al. Lancet, 2015

Spironolactone – Potassium management

• Principal concerns are – K+

– Renal function deterioration

• Hyperkalaemia more likely in patients with – Diabetes

– Reduced GFR

• Don’t start if K is >4.5 in these groups

• Caution in others, but this problem is manageable

McDonagh et al, BMJ. 2010.

Managing potassium

• Firstly, make sure your patients aren’t taking Lo Salt!

• Review diet and ensure low K • Second, consider increasing the thiazide to

offset the potassium – BFZ doses first studied were 10mg

• Third, start with 12.5mg daily and then double • Increased vulnerability to secondary insult, but

uncontrolled HT on 4+ drugs is higher risk after 14 days

• Potassium chelating agents may present niche opportunities here

When a B-Blocker? • ASCOT ended Atenolol as a first line drug

• Demonstrated that good drop of pressure in the arm, but up to 4mmHg less in the aorta

• Higher stroke rates, probably as a result of this (and higher diabetes rates)

• May still be important in patients with high renin HT

• Atenolol, though, is not nebivolol or carvedilol.

• Carvedilol did not increase the rate of diabetes in the GEMINI study (metoprolol did)

Dahlof et al, Lancet, 2005

Williams, et al. Circulation, 2006.

Simple changes that can make a difference

• In patients with tolerance issues, spread the drugs throughout the day – Diuretics morning – Vasodilators night-time

• In patients with compliance issues, avoid doxazosin • Use newer vasodilating B-Blockers instead of older agents • In patients not suitable for B-Blockers, try verapamil ahead of non-

hydropyridine CCBs • Older patients - dual diuretics (amiloride if spiro not tolerated) • If spironolactone not tolerated – eplerenone • For patients with tolerance issues, start drugs every other day (except Dox)

or at half-strength (‘micro-dosing technique’)

What is the frequency of ‘genuine’ drug resistance?

• Unclear (3-12% quoted in literature)

• Many factors feed in to a finding of ‘resistant hypertension’

• Consider this scenario: – 75 yr old lady with HT for 10 years

– BP is 180 off drugs

– On drugs, BP varies between 120 and 160

– She feels unwell when BP is 120 and so does not take her drugs regularly

• What is the cause of her ‘resistant hypertension’?

Are current hypertension strategies correct?

• Lifetime burden of hypertension reflected in level of large arterial dysfunction

• Level of arterial damage is a predictor of BP variability and outcomes

• BP variability is a predictor of drug intolerance, non-compliance, higher rates of stroke and lower rates of achieving BP targets

• This is a strong argument for tightening up early

Are current hypertension strategies correct?

• However, clinical events happen in those with risk factors that magnify significance of HT

• We could treat one person’s HT of 160 for 20 years with a low likelihood of preventing CV event

• We could ignore another person’s HT of 145 for 5 years with a higher risk of CV event

DASHER study

• Pilot study looking at accelerated management of new onset stage II/III hypertension

• Relationship of microvascular and macrovascular characteristics with ease of BP control

• Standardised secondary cause investigations for those not reaching target

• Implementing strategies for minimisation of drug with side effects

• Examine broader consequences of earlier control on CV physiology, drug compliance rates

Experimental strategies

Renal Denervation

• There are new, invasive treatments under investigation in HT

• Renal denervation remains one option that requires further study

• Recent negative trial, where sham and placebo showed similar falls in BP

• Technical issues with the trial and new trials are ongoing to see whether those issues affected results

The UK experience with RDN – 253 pts treated in 18 centres

Sharp ASP et al, Clinical Research in Cardiology, 2016

The ROX coupler

• Creates an AV fistula at the iliac artery level through percutaneous procedure

• In open label trials reduced BP by approx 27mmHg

• ?Right heart effects

• ?Attenuation

• 40% get venous stenosis requiring subsequent balloon angioplasty

Lobo et al, Lancet 2015

Carotid baroreceptor stimulation • Electrical device like a

pacemaker • Stimulates the carotid

baroreceptor, reducing sympathetic tone and BP

• Definitive study missed primary endpoint, but technical problems with that study

• Still mileage in this technology, from a procedure not so different to a PPM

Unilateral Carotid body resection

• Interesting work from Bristol

• Aimed at reduction in sympathetic nervous activity

• 15 patients treated

• Neutral effect across cohort but signal that some patients may benefit

Narkiewicz et al, JACC, 2016

There are plenty more

• Stenting of aortic arch

• Endovascular modification of carotid body with ‘stent’

• Ureteric denervation

• All in early phase of development and many of these may not make it through to clinical use.

Closing thoughts: Caveat Emptor….

What I was told on the first day of medical school

• Dean of medicine gave us a talk

• It was our first day and he told us of glorious times ahead

• And he said……

‘You can do a lot as a doctor and get away with it, but the one thing guaranteed to get you struck off is to give B-Blockers to a patient with heart failure’

There are many things to think about in that statement

• I suspect the management of hypertension will continue to evolve significantly

• Time will tell whether the current and proposed next direction of travel will prove to be the correct ones

Summary

• Combination therapy is required in significant HT • Spironolactone is the best fourth-line drug for

‘resistant’ patients • Much of ‘difficult’ hypertension management is the

prosaic pursuit of drug compliance • In those with long-standing hypertension, arterial

damage and altered auto-regulation makes control difficult and sometimes impossible (too late)

• ‘Micro-dosing’ may help in those patients • Device treatments for HT are still in the research

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