Novel stratified medicines approach to manage uncontrolled hypertension due to multiple drug intolerances

Abstract

A 61-year-old man with a 30-year history of uncontrolled hypertension was unable to tolerate conventional antihypertensive medications from all classes. At the time of referral to our centre he had discontinued all antihypertensive drugs and felt well. However, his average home blood pressure (HBP) reading was 179/125 mm Hg and echocardiography demonstrated moderate concentric left ventricular hypertrophy. A novel stratified medicines algorithm was used to guide treatment entailing transdermal clonidine patch therapy instead of tablet formulations. Sixteen months later, his average HBP was 147/106 mm Hg with no side effects and the left ventricular hypertrophy had completely regressed. Our experience has taught us that multiple drug intolerance is a common, often overlooked, cause of non-adherence to antihypertensive medication. This case demonstrates the benefit of a novel approach to optimise blood pressure control and emphasises the important role of hypertension specialists in managing complex, high-risk patients unable to tolerate guideline-based therapy.

Background

Hypertension is common and also the most preventable cause of premature cardiovascular (CV) morbidity and mortality.¹ The relative risk of mortality from ischaemic heart disease and stroke increases by 7% and 10%, respectively, with each 2 mm Hg rise in systolic blood pressure (SBP) with SBPs above 115 mm Hg.² Multiple-drug intolerant (MDI) hypertension is defined as patients who have documented intolerances to three or more unrelated classes of hypertensive medicines.³ Hypersensitivity reactions, dose-dependent side effects or reactions which are pharmacologically unpredictable, can all render patients unable to take antihypertensive medicines recommended by guidelines.⁴ This patient group is at highest risk of end-organ damage leading to fatal/non-fatal CV events and poor quality of life.⁵

Case presentation

A 61-year-old Caucasian man diagnosed with hypertension 30 years previously, was referred to the Barts blood pressure (BP) clinic for a second opinion (November 2016). His comorbidities included primary polycythaemia rubra vera (PRV) for which he was receiving yearly venesections with little effect on BP levels. He had a family history of ischaemic heart disease. His home BP (HBP) was 179/125 mm Hg and ambulatory BP monitoring demonstrated a daytime average of 182/125 mm Hg with blunted nocturnal dipping and a night-time average of 176/122 mm Hg corroborating the HBP recordings and greatly elevated CV risk. He denied taking any prescribed or over-the-counter medicines at the time of referral due to profound intolerance of all classes of antihypertensive tablets. His list of medicine intolerances included diltiazem, amlodipine, bisoprolol, candesartan, ramipril, bendroflumethiazide, doxazosin, hydralazine (associated with numbness, paraesthesia and weakness) and spironolactone (various effects including lethargy, dizziness, blackouts possibly secondary to postural hypotension requiring hospitalisation). He had never smoked, rarely drank alcohol and reported adherence to a low sodium diet. He was recently retired from his job due to feeling generally unwell, fatigued and unsafe. He reported that numerous antihypertensive medications had exacerbated these symptoms.

Investigations

Secondary causes of hypertension were ruled out with blood and urine analyses and CT imaging of the adrenals, kidneys and renal arteries. His echocardiogram was reported to show moderate left ventricular hypertrophy (LVH), indicating a very high CV risk.

Treatment

A novel stratified antihypertensive medicines algorithm, previously devised and published by our group, has evolved as part of routine care for MDI patients in the Barts BP clinic (figure 1).³ The framework is a stepwise approach: first-line therapy is fractional doses of conventional medicines;⁶ second-line therapy is to use liquid formulations of conventional medicines; third-line therapy includes transdermal patches and fourth line is the use of unlicensed medicines repurposed as antihypertensives. If these approaches are not tolerated or unsuccessful in controlling BP, the patient can be considered for device-based therapies such as renal denervation or a central arteriovenous coupler, which are available at our centre.

Figure 1.

Stratified medicines algorithm to guide treatment of multidrug intolerant hypertension. Adapted from Antoniou et al.³

Table 1 summarises the pharmacological management strategy. He was initially not keen to try additional oral antihypertensive medication in either tablet or liquid form. A trial of transdermal clonidine was therefore initiated by Barts BP clinic.

Table 1.

Treatment of the patient and substantial improvement of his blood pressure (BP) while using clonidine patch

Date	Average home blood pressure reading (mm Hg)	Management
November 2016	179/125	First clinic appointment. Commenced Catapres-TTS1: one patch, once weekly.
March 2017	169/120	Catapres-TTS2: one patch twice weekly.
December 2017	165/118	Catapres-TTS2: two patches once weekly. Excluded from trial due to PRV.
February 2018	165/117 (including readings 116/24; 122/94; 127/88; 126/89)	Catapres-TTS2: two patches every 3 days. Furosemide liquid 5 mg once daily.
March 2018	147/106	Catapres-TTS2: two patches every 3 days. Furosemide liquid 10 mg od

PRV, polycythaemia rubra vera.

The active ingredient in Catapres-TTS is clonidine, a centrally acting alpha-2 adrenoceptor agonist, which acts to reduce sympathetic outflow from the central nervous system (figure 2).⁷ This serves to reduce peripheral and renal vascular resistance, heart rate and BP. It does not affect renal blood flow or glomerular filtration rate. Orthostatic symptoms are mild and infrequent because postural reflexes are unaltered.⁷ The patch is applied to the upper thorax or outer arm for 1 week in duration. The rate of clonidine dispersal from the patch is constant for 1 week. Contraindications are known hypersensitivity to clonidine or any component of the transdermal system. Clonidine is not indicated for hypertension secondary to pheochromocytoma. Drug interactions are outlined in Box 1.⁷ It is currently unlicensed transdermally for the management of hypertension in the UK, and not referenced in the British National Formulary 75.

Figure 2.

Image of a clonidine patch. Adapted from manufacturer’s prescribing information.⁷

Box 1. Clonidine drug interactions.⁷ .

• Tricyclic antidepressants—may reduce hypotensive effects.

• Neuroleptics—may exacerbate orthostatic regulation disturbances (orthostatic hypotension, dizziness and fatigue).

• Agents known to affect sinus node function/atrioventricular node node conduction (digitalis, calcium channel blockers and beta blockers)—may cause severe sinus bradycardia.

This agent was chosen for our patient because he had both high systolic and diastolic levels indicating a markedly elevated sympathetic drive, which clonidine would act to reduce. Furthermore, alternative approaches such as device options were limited because he was excluded from research trials due to his PRV.

Our hypertension specialist advised that he might feel non-specifically unwell with lethargy that diminishes over the first couple of weeks. For this reason, patients should not drive or operate heavy machinery. The sedative effect may be increased if used with alcohol or barbiturates. A common side effect is erythema around the patch site. It was explained that should he experience this, that the patch can be removed and replaced with a new system to an alternative skin site.

Outcome and follow-up

The patient’s BP readings are reported in table 1. HBP is used in table 1 due to white coat hypertension. Within 16 months average SBP fell by 32 mm Hg and average diastolic BP (DBP) fell by 17 mm Hg to significantly reduce his stroke and ischaemic heart disease risk (112% relative reduction and 160% relative reduction, respectively). Importantly, he commented that his concentration and ability to function and quality of life were all greatly improved without notable side effects.

One year into his new treatment regimen a repeat echocardiogram demonstrated complete resolution of his concentric LVH suggesting that the HBP was indeed much better controlled. He thereafter agreed to trial liquid furosemide in addition to clonidine patches and this also resulted in improved BP levels (table 1). His most recent HBP in March 2018 was 147/108 mm Hg and there is potential to further up-titrate the clonidine patch dosage to achieve target BP.

Discussion

Despite the availability of numerous medication classes that lower BP, hypertension is inadequately controlled to guideline-recommended levels in >50% of treated patients.⁸ A major cause of poor BP control is due to poor compliance with antihypertensive drug therapy. Broadly speaking, antihypertensive medication adherence problems manifest in two ways: covertly and overtly. Covert non-adherence arises when patients claim to be taking their antihypertensive medications but are not actually taking them (for a variety of reasons).³ This has been well documented as a cause of resistant hypertension and it is apparent that the more antihypertensive drugs that are prescribed, the more likely it is to result in poor adherence.⁹ Overt non-adherence is described when patients openly admit to not complying with their medication regimens. One cause of this is multiple drug intolerances, which prevent adequate pharmacotherapy to achieve BP control as in this particular case report.³

At present hypertension guidelines around the world refer to how to manage covert and overt non-adherence when considering fixed dose or single pill combinations. However, MDI hypertension is often overlooked as a cause of overt non-compliance. To date, published evidence of effective treatment approaches in this patient group is very limited despite their substantial unmet need with high CV risk and poor quality of life.^{1 2}

We have previously reported a case series to illustrate how the different steps of our novel treatment algorithm have been successfully deployed.¹⁰ In terms of the clinical efficacy of transdermal clonidine in BP control in this patient group, we have demonstrated in a 36-patient trial a reduction in clinic SBP of 23±33 mm Hg (p<0.001) and a reduction in clinic DBP of 10±18 mm Hg (p=0.002) over a duration 11 weeks with a good tolerability profile.

Specialist hypertension clinics are able to offer alternative treatment strategies for patients with MDI hypertension who have no conventional options to achieve BP control, yet there are only 40 accredited hypertension specialists in the UK! Details of the centres are available on the European Society of Hypertension, British and Irish Hypertension Society websites.

Patient’s perspective.

Since the age of 32, I have experienced bouts of side effects from antihypertensive medications including excessive tiredness, blackouts, dizziness, temporary amnesia (it took a year to fully recover from amnesia), extreme tiredness and muscle weakness. The excessive tiredness affected my working life and I was also falling asleep walking along the road.

Due to continued health problems I had to retire from work in September 2014. By then I had a long period of extreme muscle weakness and had to use a stick to get around. Furthermore, I had to attend the medical centre at work, and, it seemed, to be allowed to work I had to take BP tablets.

My General Practitioner (GP) explained that the tablets were not solving my BP and health problems. He could clearly see that I had intolerance and felt he could no longer help me. With agreement with the GP, it was agreed that I stop taking the BP tablets. He referred me to a renal specialist at my local District General Hospital. This was when things got worse. The first doctor I met here was more obstinate than my GP and despite trying me on different tablets did not want to give up finding the right one.

Following various tests I was put on a course of hydralazine in July 2015. Within a few days I experienced paralysis, extreme swelling of the hands and severe chest pain. I contacted the renal doctor and I was advised to stop the medication. After stopping these tablets, my BP was averaging around 200/160 mm Hg. However, I did not have any chest pain, my muscle strength had come back and walking was good. I felt so much better!

In August 2016, I saw another nephrology consultant. We discussed how much better I felt, and although my BP was good at this time (170/110 mm Hg) he offered me doxazosin. I explained to him that this had previously caused severe side effects. At this point I was accused of refusing medication. I decided to seek a second opinion at Barts BP clinic, as there was no alternative except tablets that I had previously taken with side effects. The medication I had tried so far included diltiazem, amlodipine, atenolol, bisoprolol, candesartan, ramipril, bendroflumethiazide, doxazosin, and gydralazine.

The approach at Barts was that one size does not fit all. I appreciated the way the team listened to me and explained what to try next. The most important thing that I have found is the honesty, even if there is no other alternative at that point in time. My wife feels very confident in the way I am being treated and no longer gets very stressed when I go for appointments.

Once I started the Clonidine TTS1 and then TTS2 patches, I saw a lowering of my BP. I will admit that I was doubtful and thought that once my body got too used the patches, the patches would become ineffective. So far though, so good! Furosemide has also been a great help and at present, I have had no side effects. I would lastly like to say that I am no longer stressed before my appointments, and I am sure that this has also helped my BP. Many thanks for all the support and help I get from the team at Barts BP clinic.

Learning points.

• Adverse effects of drugs are a common cause of poor adherence to antihypertensive medication regimens resulting in failure to control blood pressure (BP) to target in large numbers of patients.

• A subset of patients exhibit intolerance to multiple antihypertensives of different classes and present with uncontrolled hypertension and very high cardiovascular risk for which there is no established guidance to aid clinician management.

• A novel stratified medicines algorithm has been shown to help treat hypertension in the setting of multiple-drug intolerant and uses fractional tablet dosing/liquid formulations/patch formulations of antihypertensive drugs.

• Patients whose BP cannot be managed according to conventional guidelines should be referred to hypertension specialists who have access to novel medication or device treatment options.