The role of single pill combination therapy in the prevention of ischaemic stroke

Abstract

Background and aims

The role of single pill combination therapy for stroke prevention remains to be established. We explored the perspectives of stroke survivors and healthcare professionals on single pill combination therapy for stroke prevention.

Methods

We conducted focus groups involving stroke survivors and healthcare professionals.

Results

We recruited six stroke survivors: four (67%) were female and mean age was 70 ± 12 years; and eight healthcare professionals (three Stroke Consultants, two Nurse Specialists, three General Practitioners). Improved adherence is the main perceived benefit of single pill combination therapy, although concerns exist surrounding less individualised care, unsuitability for use in the acute setting, reduced ability to titrate doses and difficulty identifying the cause of side effects. The clinical stability of patients, alongside single pill combination therapy efficacy, cost, side effect profile and evidence base for impact on risk factors and clinical outcomes are key factors influencing acceptability. Stroke survivors and healthcare professionals feel single pill combination therapy is most suitable for stable patients, although there is no evidence base for its use in this context.

Conclusion

Stroke healthcare professionals and stroke survivors are most amenable to using single pill combination therapy for stable patients, although its role in this context should be evaluated in studies with risk factor targets and clinical outcomes as endpoints.

Keywords

Stroke stroke prevention single pill combination therapy focus groups

Introduction

Single pill combination (SPC) therapy with more than one drug in a single pill¹ improves concordance in patients with or at high risk of cardiovascular disease (CVD).^2,3 Some European guidelines emphasise the use of SPC therapy for management of high blood pressure (BP) and secondary prevention of myocardial infarction (MI).^4,5 Despite improved concordance, the effects of SPC therapy on cardiovascular risk factors and outcomes remain less clear. Indeed, SPC therapy has been shown to improve concordance in patients with previous MI, but has no additional effect on BP or cholesterol,⁶ while SPC has been shown to improve concordance, BP and cholesterol among patients with or at high risk of CVD, but with a trend to increase cardiovascular events.³ Concordance with preventive medication remains a challenge following stroke and declines by up to 50% in the two years after diagnosis.^7,8 The role of SPC therapy in stroke prevention remains to be established and there is a need to understand opinions surrounding its use in this context. We therefore explored the views of stroke survivors and healthcare professionals (HCPs) on SPC therapy for the prevention of ischaemic stroke.

Patients and methods

Study design

We conducted focus groups involving stroke survivors and HCPs. Grounded Theory was the general theoretical framework, which involves using all related materials to generate concepts.^9–11 Focus group data, clinical guidelines from the European Stroke Organization, American Heart Association/American Stroke Association, Scottish Intercollegiate Guidelines Network and Royal College of Physicians,^12–15 and patient information leaflets from Chest Heart and Stroke Scotland, the Stroke Association and NHS England were explored.^16–19

Participants

We recruited HCPs involved in the care of stroke survivors (general practitioners (GPs), stroke physicians and stroke nurse specialists); and stroke survivors aged 18 years or over with a clinically confirmed diagnosis of non-cardioembolic ischaemic stroke or transient ischaemic attack in the previous six months to five years who were fluent English speakers and could provide informed consent. A mixture of convenience and purposive sampling was used to facilitate variation in participant characteristics. HCPs were identified by professional networks and stroke survivors were approached by members of the research team involved in their care or by invitation letter. Stroke survivors were reimbursed £20 to cover travel expenses and time.

Data collection and analysis

Semi-structured focus groups were conducted separately for stroke survivors and HCPs. These lasted 1 h and were moderated by a member of the research team. Topics explored include challenges in stroke prevention and factors influencing acceptability of SPC therapy. The audio recording of each focus group was transcribed as a practical variant on Grounded Theory.⁹ A set of codes representing key concepts was created in advance and modified following the focus groups. Transcripts were coded and the constant comparative method was used to develop a substantive theory.²⁰

Ethical approval

The study was approved by the West of Scotland Research Ethics Committee 5 and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

Results

Study participants

The focus groups involved six stroke survivors and eight HCPs (Tables 1 and 2).

Table 1.

Demographics of stroke survivors.

Demographic variable	Stroke survivors (n = 6) n (%)
Sex (female)	4 (67%)
Age (mean, SD; years)	70 (±12)
Ethnic origin
Caucasian	4 (67%)
Stroke classification
Ischaemic stroke	4 (67%)
Transient ischaemic attack	2 (33%)
Time since stroke
6 months – 1 year	5 (83%)
1 year – 2 years	1 (17%)
Risk factors
Hypertension	6 (100%)
Hypercholesterolaemia	3 (50%)
Diabetes mellitus	1 (17%)
Current smoker	1 (17%)
Ex-smoker	3 (50%)

Table 2.

Demographics of healthcare professionals.

Demographic variable	Healthcare professionals (n = 8) n (%)
Sex (female)	2 (25%)
General practitioner	3 (38%)
Stroke physician	3 (38%)
Stroke nurse specialist	2 (25%)

Challenges in stroke prevention

HCPs identified limited resources and non-concordance as the main challenges in stroke prevention, while low support and medication side effects were the main difficulties described by stroke survivors.

Non-concordance

Two GPs associated non-concordance with polypharmacy and self-rationalisation of medications that do not improve symptoms or which cause side effects.

… you’re on nineteen different medicines. I think patients start looking … and say “Okay, what are the ones that I really need?” I think prevention ones … are the first to go. (HCP 8, GP)

Patient support

Three stroke survivors described a lack of information about preventive medications before discharge and low input from GPs thereafter, while two stroke survivors felt medication leaflets and stroke information packs were of limited use.

There’s got to be more involvement from doctors at your surgery … (Stroke survivor 3)

I tried to read the leaflet inside to find out why I am taking them. I don’t know the difference between a blood pressure (BP), cholesterol or blood-thinning tablet … (Stroke survivor 3)

Resources

All stroke physicians felt inadequate time led to challenges communicating the need for preventive medication. The importance of GPs, pharmacists and practice nurses to conduct follow-up after discharge was highlighted.

I think in hospital … you get the time to start them on secondary prevention, but you probably don’t get the time to go through the reasoning … (HCP 5, Stroke Physician)

Side effects

Two stroke survivors described challenges related to side-effects.

I had to stop taking the statins, because I got so sore and so weak … I would rather have better quality of life than be living longer. (Stroke survivor 1)

SPC therapy for stroke prevention

Both HCPs and stroke survivors perceive improved concordance as the main potential benefit of SPC therapy, but have concerns surrounding the suitability for use in the acute setting, less individualised care, difficulty identifying the cause of side effects and reduced flexibility to adjust drug doses. HCPs also have concerns surrounding the impact of SPC therapy on risk factor targets and clinical outcomes. Overall, acceptability was influenced by patient stability alongside drug cost and efficacy (Figure 1).

Figure 1.

Factors influencing acceptability of single pill combination therapy in healthcare professionals (n = 8, orange bars) and stroke survivors (n = 6, green bars).

Perceived benefits

The impact of SPC therapy on pill burden and concordance was the main potential benefit identified by four HCPs and three stroke survivors.

I can see the benefit in terms of concordance and cutting down the burden of pill-taking. (HCP 7, Stroke Nurse)

Some people are on ten, fifteen medicines … if you want to talk about improving concordance … I think if you are stabilised and well, why not have combination of things? (HCP, GP)

… it said that one pill would cover everything. I thought “Brilliant!” Instead of having to take this one and that one at such and such a time. (Stroke survivor 1)

I take so many tablets … I couldn’t remember whether I was taking one, two; am I taking them on time? [it] will be very good if you have them all in one. (Stroke survivor 2)

Concerns

Early initiation

Stroke survivors and HCPs expressed concerns over initiating SPC therapy in the acute setting.

I share some of the concerns about when people are at a very acute and unstable phase of an illness … I would worry, just because there’s too many things going on. (HCP 2, Stroke Physician)

I was only in [hospital] for two days, so they can’t really judge what the medication is doing. (Stroke survivor 1)

Less individualised care

Stroke survivors and HCPs questioned the suitability of a “one size fits all” approach and two HCPs felt SPC therapy would reduce the value of risk stratification.

Hopefully there’s added value from all the risk stratification that we do … it is then you tailor the choice. (HCP 5, Stroke Physician)

I can’t see it being something … saying everyone who’s going home with diagnosis X gets the polypill. (HCP 7, Stroke Nurse)

Side effects and dose adjustment

Challenges in identifying the component causing side effects were a concern for two HCPs. Three stroke survivors were concerned about reduced ability to adjust doses.

… if you get side effects … it is nice to be able to work backwards and extract the culprit. (HCP 5, Stroke Physician)

If it goes wrong, it’s really difficult to establish what is going wrong. (HCP 7, Stroke Nurse)

You have more flexibility on the dosage with individual drugs. (Stroke survivor 3)

Non-concordance

Two HCPs and one stroke survivor felt there was a risk of patients omitting all medications if they were non-adherent with SPC therapy.

If you change to one [pill] and then are non-compliant with that … they are not taking anything. (HCP 4, Stroke Physician)

Factors influencing acceptability

Cost

Three HCPs would feel hesitant in using SPC therapy if it was more expensive than prescribing the individual components separately.

You would struggle to convince me to prescribe it [if the poly-pill was more expensive than three existing agents]. (HCP 1, GP)

Efficacy

Two stroke survivors felt SPC therapy would need to be of equivalent efficacy to their current regimen. The importance of effective BP and lipid-lowering was highlighted by stroke survivors.

I will be scared if I am going to get something that is not as good as what I am already taking … (Stroke survivor 2)

If they could cover BP and cholesterol … if there was one pill that would cover that then that would be better. (Stroke survivor 1)

Side effects

Two stroke survivors felt minimal side effects is important.

If there are no side effects, I can’t see the harm. (Stroke survivor 3)

Patient stability

Seven HCPs were open to the possibility of transitioning stable patients to SPC therapy once confidence in individual drugs was established, which was endorsed by two stroke survivors.

It’s probably not necessary for the sort of acute, post-stroke stage. It is for the chronic disease management a bit down the line. (HCP 1, GP)

Try the individual medications and if you then find them acceptable … .you could perhaps transition them to a single pill. (HCP 2, Stroke Physician)

I think having it for that situation as an option on the table might help with concordance and improve patient experience in stable disease. (HCP 5, Stroke Physician)

Evidence base

Stroke physicians felt GPs could transition stable patients to SPC therapy. All three GPs and two stroke survivors described the need for an evidence base demonstrating safety.

The problem is that you need the data to show that they can be switched further down the line. (HCP 1, GP)

Overall perspectives

Six HCPs felt uncomfortable with the concept of SPC therapy at the start of the focus group. At the end of the focus group, six out of eight HCPs were amenable to prescribing SPC therapy in stable patients (Figure 2), whereas the opinions of stroke survivors remained variable throughout (Figure 3).

Figure 2.

Acceptability of single pill combination therapy among healthcare professionals at the beginning of focus group (blue bars) and end of focus group (orange bars); n = 8.

Figure 3.

Acceptability of single pill combination therapy among stroke survivors at the beginning of focus group (blue bars) and end of focus group (orange bars); n = 6.

Patient information leaflets

All patient leaflets^16–19 emphasise the importance of preventive medication by describing their role in reducing cardiovascular risk factors. The need for anti-platelet therapy is clearly communicated, although there is less emphasis on cholesterol and BP-lowering medications and no leaflet mentions SPC therapy.^17,18

Clinical guidelines

All guidelines for secondary prevention of stroke^12–15 recommend anti-platelet, statin and anti-hypertensive medications, although none discuss SPC therapy.

Discussion

Stroke survivors and HCPs believe improved concordance is the main potential benefit of SPC therapy but have concerns surrounding reduced ability to titrate doses, difficulty identifying the cause of side effects and the need for evidence demonstrating impact on risk factors and clinical outcomes. While our results are broadly in keeping with the views of GPs, caregivers and stroke survivors from another UK study,²¹ a novel finding is that SPC therapy may be most suitable for use in stable patients, although an evidence base does not exist for its use in this context.

Efficacy was identified as an important factor influencing the acceptability of SPC therapy in stroke survivors and our participants question a “one size fits all” approach, which is supported by an emphasis on individualised care in patient information leaflets and clinical guidelines.^12–19 SPC drugs with the most efficacious and evidence-based anti-platelet, BP and cholesterol-lowering components, and doses that can be adjusted, could address these points, although this appears aspirational.^22,23 The additional cost to drug manufacturers may be a barrier since many stroke prevention drugs are generic and there may be little incentive for drug developers. HCPs felt SPC therapy must cost similar to prescribing the individual components, since any increase in drug cost would need to be offset by savings from effects on clinical outcomes that may be challenging to achieve.^24,25

While SPC therapy may improve concordance, the ability of SPC therapy to deliver clinical outcomes that are consistent with, or superior to, standard care remains uncertain. Effects on BP and lipid profile are variable and concerns exist surrounding the impact of SPC therapy on the incidence of major cardiovascular events.^3,6 Indeed, SPC therapy was associated with a 22% absolute increase in adherence in a randomised trial of patients with or at high risk of CVD, yet had a near-significant trend to increased risk of cardiovascular events.³ While the authors suggest this may be due to the trial not being powered to detect differences in cardiovascular events,³ the topic merits further evaluation. Thus, while it has been suggested that evaluation of SPC therapy could be based on bioequivalence and adherence,^3,26 it will be essential to ensure future trials also assess the impact on clinical outcomes.⁶

Initiation of SPC therapy in the acute setting is a major concern that was not identified in previous studies.^21,22,27 Dual-antiplatelet therapy is commonly used in the early management of high risk transient ischaemic attack or minor ischaemic stroke,^28,29 and would not be possible with current SPC therapy. The ability to monitor effects from SPC therapy on renal function and BP during a potentially short inpatient admission is a further concern expressed by patients and HCPs. Side effects are a major factor influencing concordance, and intolerance of SPC therapy could lead to discontinuation of all components and worse outcomes than traditional care.^30–32 Thus, patient stability is a major factor influencing acceptability and SPC therapy may be most suitable for stable patients. However, there is no current evidence base for its use in this context and this should therefore be evaluated in clinical trials with risk factor targets and clinical outcomes as endpoints.

Strengths and limitations

A major strength of our study is the inclusion of stroke physicians and nurse specialists, as previous studies only included GPs.²¹ Our sample size is small, and we only included stroke survivors who could attend a focus group. The views may not represent stroke survivors with more severe disability in whom greater medication ease and convenience may be most beneficial.⁵ We included stroke survivors with non-cardioembolic ischaemic stroke as current SPC therapy formulations do not include anticoagulants and our findings cannot be extrapolated to patients requiring oral anticoagulation.¹³

Conclusion

SPC therapy improves concordance and may have a role for stroke prevention in stable patients, but a number of concerns exist. Patient stability alongside drug efficacy, cost, side effect profile and an evidence base for effects on risk factors and clinical outcomes are the main factors influencing acceptability. HCPs are most amenable to using SPC therapy for stable patients, although there is no current evidence base for its use in this context and future studies should evaluate this, with risk factor targets and clinical outcomes as endpoints.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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