Polypill, hypertension and medication adherence: The solution strategy?

Polypill, hypertension and medication adherence: The solution strategy?

IJCA-25710; No of Pages 6 International Journal of Cardiology xxx (2017) xxx–xxx Contents lists available at ScienceDirect International Journal of ...

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IJCA-25710; No of Pages 6 International Journal of Cardiology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Polypill, hypertension and medication adherence: The solution strategy? D. Cimmaruta a,1, N. Lombardi b,1, C. Borghi c, G. Rosano d,e, F. Rossi a, A. Mugelli b,⁎ a

Department of Experimental Medicine, Section of Pharmacology “L. Donatelli”, University of Campania Region “Luigi Vanvitelli”, Naples, Italy Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy c Atherosclerosis Research Unit, Medicine & Surgery Sciences Dept., Alma Mater Studiorum University of Bologna, Bologna, Italy d IRCCS San Raffaele Pisana, Rome, Italy e Cardiovascular and Cell Sciences Research Institute, St. George's University of London, London, United Kingdom b

a r t i c l e

i n f o

Article history: Received 11 May 2017 Received in revised form 18 September 2017 Accepted 21 November 2017 Available online xxxx Keywords: Adherence Polypill Hypertension Systolic blood pressure LDL-cholesterol Cardiovascular events

a b s t r a c t Introduction: Hypertension is an important global health challenge and a leading preventable risk factor for premature death and disability worldwide. In current cardiology practice, the main obstacles in the management of patients affected by hypertension are comorbidities and poor adherence to pharmacological treatments. The World Health Organization has recently highlighted increased adherence as a key development need for reducing cardiovascular disease. Methods: Principal observational and clinical trial data regarding adherence, reductions in cardiovascular risk and safety of the polypill approach are summarized and reviewed. Conclusions: The polypill approach has been conclusively shown to increase adherence relative to usual care in all cardiovascular patients, furthermore, concomitant risk factor reductions have also been suggested. To date, the use of polypill could represent a solution strategy in patients affected by hypertension, comorbidities and non-adherence even though further studies, especially in the real-world settings, are needed in order to better understand its role in clinical practice. © 2017 Elsevier B.V. All rights reserved.

1. Background Hypertension is an important global health challenge and a leading preventable risk factor for premature death and disability worldwide [1]. The management of hypertension has two main aims: obtaining optimal blood pressure (BP) levels and reducing cardiovascular events and mortality. Therapeutic arsenal for treatment of hypertension includes angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs or sartans), β-blockers, calcium channel blockers (CCBs) and diuretics [2]. ESH-ESC 2013 guidelines recommend to start antihypertensive treatment with diuretics, β-blockers, CCBs, ACE inhibitors and sartans, either alone or in combination. Different pharmacological associations can be considered, in particular ACE inhibitor and diuretic, sartan and diuretic, ACE inhibitor or sartan and CCB [3]. Pharmacological intervention is required when systolic BP (SBP) value is above 160 mm Hg and the goal of treatment is represented by the progressive achievement of values lower than 140 mm Hg. However, the achievement of this

⁎ Corresponding author at: Department of Neurosciences, Psychology, Drug Research and Child Health, Viale G. Pieraccini, 6, 50139 Florence, Italy. E-mail address: [email protected]fi.it (A. Mugelli). 1 Contributed equally.

value is often difficult and b 25% of the patients reported values below 140/90 mm Hg. In current cardiology practice, the main obstacles in the management of patients affected by hypertension are comorbidities and poor adherence to pharmacological treatments [4]. 2. Treatment of hypertension and comorbidities Treatment of hypertension could be complicated by several comorbidities (e.g., diabetes mellitus, kidney disease, cardiovascular diseases) and, in the real-world population, its management is a matter of debate [5]. Several drugs can be administered in patients with hypertension and comorbidities (ACE inhibitors, sartans, diuretics, β-blockers, CCB) and the choice strictly depends on patient characteristics, comorbidities and risk factors (Table 1). Different BP target values have been proposed for diabetic patients in order to minimize cardiovascular risk. Few randomized controlled trials have shown that a reduction of SBP to levels of 120–125 mm Hg and/or to 70–75 mm Hg diastolic BP (DBP) could lead to an increased incidence of coronary events, consequent to hypoperfusion of vital organs (the so called “J-curve phenomenon”) [6]. In the light of these findings, the previous target of ≤ 130/80 mm Hg is no longer evidence based. Nevertheless, there is still no homogeneity regarding optimal BP targets. In fact, recent international guidelines [7,8] suggest to start treatment when BP values are ≥ 140 mm Hg (SBP) and ≥ 90 mm Hg (DBP) with

https://doi.org/10.1016/j.ijcard.2017.11.075 0167-5273/© 2017 Elsevier B.V. All rights reserved.

Please cite this article as: D. Cimmaruta, et al., Polypill, hypertension and medication adherence: The solution strategy?, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.11.075

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D. Cimmaruta et al. / International Journal of Cardiology xxx (2017) xxx–xxx

Table 1 Blood pressure values and comorbidities. Guidelines

Population

BP target (mm Hg) Pharmacological treatment

Age ≥ 60 years Age b 60 years Diabetes Chronic kidney disease ESH/ESC 2013 [3] Young adults Age ≥ 80 years Age b 80 years Diabetes Chronic kidney disease without proteinuria Chronic kidney disease with proteinuria American Diabetes Association (ADA) 2016 [8] Diabetes Kidney Disease: Improving Global Outcome Chronic kidney disease without proteinuria (KDIGO) 2013 [10] Chronic kidney disease without proteinuria National Institute for Health and Clinical Excellence Age ≥ 80 years (NICE) 2014 for chronic kidney disease and 2015 Age b 80 years Type 2 diabetes without macrovascular for diabetes [11] complications Type 2 diabetes with macrovascular complications Type 1 diabetes Type 1 diabetes with complications Chronic kidney disease JNC 8 [12]

the aim to reduce SBP b140 mm Hg and DBP b 90 mm Hg and, if patients present vascular complications, to achieve a BP target of b130/80 mm Hg. In these patients, therapy can be started with any antihypertensive medication even if combination therapy is often required to obtain optimal BP levels. ACE inhibitors or sartans should be included in any case, since they exert a protective role in renal disease; subsequently a thiazide diuretic or a CCB can be added if BP levels are not in target with ACE inhibitors or sartans alone [9]. Thiazide diuretics are often administered in combination to drugs acting on renin-angiotensin system (RAS). CCBs have proven useful, especially when combined with a RAS blocker [3]. In patients with diabetic kidney disease and concomitant proteinuria, ESH-ESC 2013 guidelines recommend a SBP reduction of b130 mm Hg, as long as the glomerular filtration rate is monitored. Similar BP target has also been suggested by the Kidney Disease: Improving Global Outcomes (KDIGO) [10], NICE [11] and JNC 8 guidelines [12]. RAS blockers seem to be more effective compared to placebo or other antihypertensive treatment in reducing albuminuria. More controversial are the recommendations for hypertensive haemodialysis patients, since the optimal target pressure is not yet clear. However, all antihypertensive drugs, with the exception of diuretics, can be used, adjusting the dosage in relation to haemodynamic conditions [3]. The context is completely different for the treatment of hypertensive patients with cardiovascular diseases (i.e., atrial fibrillation, myocardial infarction, heart failure, arterial disease). To date, there are no clear evidences in favor of the achievement of SBP values b 130 mm Hg in hypertensive patients with coronary artery disease (CAD). However, the SPRINT study demonstrated that among patients at high risk for cardiovascular events, targeting a SBP of b 120 mm Hg, as compared with b140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause [13]. In this group of patients, the cardiovascular risk reduction depends on the appropriate selection of cardiovascular medications other than the achievement of the optimal BP target [3]. In particular, for hypertensive patients with atrial fibrillation (AF) and rapid ventricular response rate, ESH/ESC guidelines recommend the use of β-blockers and non-dihydropyridine CCBs [3]. Treatments with ACE inhibitors and sartans are equally effective in reducing AF in patients with heart failure (HF) [14]. Moreover, both ACE inhibitors and sartans proved to be effective in reducing the risk of new AF, with more robust data for sartans [15]. All antihypertensives medications can be helpful in patients with CAD, but β-blockers and

b150/90 b140/90 b140/90 b140/90 b140/90 b150/90 b150/90 b140/85 b140/90 b130/90 b140/90 ≤140/90 ≤130/80 b150/90 b140/90 b140/80

Thiazide diuretics, ACE inhibitors, sartans, CCBs

ACE inhibitors, ARB Diuretics, ACE inhibitors, sartans, β-blockers o CCBs ACE inhibitors or sartans

ACE inhibitors or sartans ACE inhibitors or ARB Patients ≥55 years, CCBs Patients b55 years, ACE inhibitors or sartans ACE inhibitors, sartans thiazide diuretics, or CCBs.

b130/80 b135/85 b130/80 b140/90

ACE inhibitors, sartans, thiazide diuretics or CCBs ACE inhibitors or sartans

ACE inhibitors demonstrated a superior efficacy in patients with recent myocardial infarction (MI) [3]. In particular, β-blockers exert a positive effect in secondary prevention of MI and sudden cardiac death [16]. Moreover, β-blockers and CCBs are to prefer in case of symptomatic angina. Lastly, ACE inhibitors, diuretics and sartans can slow the progression from HF with preserved ejection fraction to HF with reduced EF and are to be preferred in this kind of patients [3]. 3. Hypertension and medication adherence Adherence to treatment may be defined as the extent to which the patient's history of therapeutic drug-taking coincides with the prescribed treatment (taking practitioner-prescribed medication N 80% of the time). Non-adherence in antihypertensive treatment could influence clinical outcomes and represents one of the major risk factors for cardiovascular complications, mainly in patients with comorbidities [17]. Therefore, maximizing adherence to antihypertensive treatment is one of the main goals in order to better control clinical outcome in hypertensive patients. Several factors are associated with non-adherence, e.g. young age, low income, multiple pharmacological treatment or being a new user of the drug. A cohort study [18] pointed out that non-adherence to any antihypertensive medication was more frequent in people under the age of 65 and with low income. Furthermore, non-adherence was higher among new users of antihypertensives and in patients taking multiple cardiovascular drugs [19]. Another retrospective cohort study found a significant relation between antihypertensive and antidyslipidemic treatments and the number of prescribers, suggesting that continuity of medication management could be improved by minimizing the number of prescribers involved in a patient's care and by ensuring optimal communication and coordination among prescribers [20]. Adherence could also be different according to drug classes. An Italian prospective study evaluated adherence to antihypertensive treatment in 347 patients. In this study, hypertensive patients were randomly allocated to monotherapy with either ACE-inhibitors, sartans, CCBs, β-blockers or diuretics. After a follow up period of 24 months, persistence of treatment was highest among ACE-inhibitors (64.5%) and sartans (68.5%), when compared to CCBs (51.6%), β-blockers (44.8%) and diuretics (34.4%) [21]. Several interventions in order to improve adherence have been evaluated, e.g. simplification of pharmacological regimens, education and

Please cite this article as: D. Cimmaruta, et al., Polypill, hypertension and medication adherence: The solution strategy?, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.11.075

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support to patient, development of health programs for assistance to patients [22]. A prospective study described medication adherence and its intensification in a physician-pharmacist collaborative management (PPCM) model, in comparison with usual care. 539 patients were enrolled in the study, and 345 out of them received the intervention with no significant differences in adherence after 9 months of follow-up [23]. A randomized trial investigated the effectiveness of a multifaceted pharmacist intervention in a hospital setting to improve medication adherence in hypertensive patients [24]. 532 patients were enrolled from 3 hospital outpatient clinics and randomized to usual care or a 6-months pharmacist intervention (e.g., medication review, adherence counseling, motivational interviewing and telephone follow-ups). At 12 months, 20.3% of the patients in the intervention group (n = 231) were non-adherent (MPR b0.80), compared with 30.2% in the control group (n = 285). Results show a significant impact on BP control and clinical outcomes, such as hospitalization and combined endpoint of cardiovascular death, stroke and MI. New initiatives to promote medication adherence could be represented by eHealth solutions (electronic communication and health information technology in health care practice) [25]. These strategies have been shown to improve self-management, adherence to lifestyle modifications, and medical therapy. A multicenter randomized trial evaluated a smartphone application (“app”) in order to improve treatment adherence in patients at high cardiovascular risk [26]. 174 patients, treated with ticagrelor, were randomized to either an interactive patient support tool (active group) or a simplified tool (control group) in addition to usual care. After 6 months follow-up, the adherence was statistically significant higher in the active group vs the control group (nonadherence score: 16.6 vs 22.8). A further method to improve adherence is the association of antihypertensive drugs in the same pharmaceutical formulation [17]. A high adherence to antihypertensive treatment could reduce not only complications and hospitalizations but also adverse events due to treatments. Therefore, educate and properly instruct patients on the treatment regimen is an important challenge that requires attention by all healthcare professionals, thus, it is crucial to the achievement of therapeutic success. 4. The polypill: a strategy for the achievement of BP target and medication adherence? Nowadays, multiple fixed-dose combination (FDC) polypills are available with differing active components. In general, each polypill is composed of a minimum of a statin, an antiplatelet drug (commonly aspirin) and an antihypertensive agent (ACE inhibitor/ARB/thiazide/ β-blocker/CCB). A range of studies assessing safety, efficacy, adherence and cost effectiveness of the polypill has been performed. Principal randomized clinical trials on polypill are reported in Table 2. In 2003, Wald and Law [27] proposed for the first time a combination (which they called polypill) containing three BP lowering drugs, from different classes each at half doses, plus aspirin, statin, and folic acid for all individuals with established cardiovascular disease (CVD) or without CVD and older than 55 years. Authors estimated that polypill, compared with placebo, reduced ischemic heart disease events by 88% and strokes by 80%, and suggested that polypill could be used without considering concomitant risk factors. Same authors, over ten years later, conducted a randomized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50+ without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs [28]. Patients took the Polypill (amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg and simvastatin 40 mg) and a placebo in random sequence. After 12 weeks, the Polypill resulted in the predicted reductions in blood pressure (the mean SBP was reduced by 17.9 mm Hg).

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Another important example was the TIPS study [29] that randomized 2053 individuals, aged 45 to 80 years without CVD and with at least one risk factor, to the Polycap, consisting of thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg), or to 8 other groups (aspirin alone, simvastatin alone, hydrochlorothiazide alone, 3 combinations of 2 BP-lowering drugs, 3 BP-lowering drugs alone, 3 BP-lowering drugs plus aspirin) administered for 12 weeks. Compared with patients not receiving BP-lowering drugs, those receiving Polycap had a reduction of systolic and diastolic BP of 7.4 and 5.6 mm Hg, respectively. In a double blind placebo-controlled trial [30], a total of 475 low-risk participants without cardiovascular disease or cardiovascular risk factors, aged 50 to 79 years, were randomized to a FDC pill (aspirin 81 mg, enalapril 2.5 mg, hydrochlorothiazide 12.5 mg and atorvastatin 20 mg) or placebo for a period of 12 months. The trial showed that, regarding to baseline BP differences, polypill was associated with statistically significant reductions in BP. In the randomized double-blind placebo controlled ‘Programme to Improve Life and Longevity’ (PILLpilot) trial [28], 378 individuals at intermediate risk of CVD were randomized to using an FDC (aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) or placebo during 12 weeks. The group treated with polypill had a mean SBP reduction of 10 mm Hg (95% CI 8 to 12). ‘The Second Indian Polycap Study’ (TIPS-2) enrolled 518 patients and demonstrated that a full-dosed polycap (with potassium supplementation) reduced SBP compared with a low-dose one, after eight weeks [31]. More recently, the ‘Use of a Multidrug Pill In Reducing cardiovascular Events’ (UMPIRE) compared a polypill-based treatment to usual care among participants with established CVD. The FDC contained aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide 12.5 mg. After a median follow-up of 15 months, the polypill improved adherence (relative risk of being adherent 1.33; 95% CI 1.26 to 1.41) with a concurrent 2.6 mm Hg (95% CI 1.1 to 4.0) reduction of SBP compared to the usual care group [32]. The Phase 1 FOCUS (Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention) study [33] evaluated factors that interfere with appropriate adherence to CV medications for secondary prevention after acute MI. Additionally, 695 patients were randomized to polypill (containing aspirin 100 mg, simvastatin 40 mg, and ramipril 2.5, 5, or 10 mg) or the three drugs given separately. Over a period of 9 months, medication adherence improved in the polypill group. In the ‘IMProving Adherence using Combination Therapy’ (IMPACT) trial, 513 patients were randomized to FDC based care or usual care. After 12 months of treatment, a higher adherence to therapy was observed in the group of patients treated with FDC treatment compared to standard therapy (81% vs 46% p b 0,001) [34]. The ‘Kanyini-Guidelines Adherence with the Polypill’ (GAP) trial showed similar results. After a median of 18 months, a greater adherence was observed in the group of patients taking the polypill compared with standard therapy [35]. In the PAINT study (perindopril-indapamide combination Amlodipine plus for controlled hypertension Non-intervention trial), it was observed that a triple combination of an ACE inhibitor, a dihydropyridine CCB and a diuretic allows the achievement of optimal BP control [36]. In patients with resistant hypertension, the PIANIST study (perindopril-indapamide plus amlodipine in high risk hypertensive patients) showed that the switch to the perindopril/indapamide and a dihydropyridine CCB treatment led to an optimal office BP control in 72% of patients [37]. A systematic review found that polypill improved adherence of 33% compared to usual care for cardiovascular disease prevention [38]. In a randomized crossover trial, the TEMPUS study, 78 patients were randomly allocated to the use of polypill (aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in the

Please cite this article as: D. Cimmaruta, et al., Polypill, hypertension and medication adherence: The solution strategy?, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.11.075

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Table 2 Overview of principal randomized clinical trials on polypill. Authors, year

Trial name

Design

Patients

Study groups

Study duration

Outcomes

Yusuf S et al., 2009 [29]

TIPS 1

Randomized, double-blind

2053 individuals without CVD with one risk factor

Polypill vs. eight other usual care groups

16 weeks

Malekzadeh F et al., 2010 [30] Rodgers A et al., 2011 [42]



Randomized, placebo-controlled, double-blind Randomized, double-blind, placebo-controlled

475 participants without CVD

Polypill vs. placebo

12 months

LDL-C, SBP, heart rate, urinary 11-dehydrothromboxane B2 and rates of discontinuation at follow-up Effects on LDL-cholesterol, systolic and diastolic blood pressure

378 patients with ≥7.5% estimated 5-year CVD risk

Polypill vs. placebo

12 weeks

Wald DS et al., 2012 [28]

Wald et al., 2012

86 patients aged 50 years or over with no history of CVD

Polypill vs. placebo

12 weeks

Yusuf S et al., 2012 [31]

TIPS 2

Randomized, placebo-controlled, double-blind, crossover Randomized, double-blind, 2 × 2, factorial, controlled

518 patients with previous CVD or diabetes mellitus

Single-dose polypill plus placebo or two polypill capsules plus K+

8 weeks

Thom S et al., 2013 [32]

UMPIRE

Randomized, open-label, blinded end-point

2004 patients with or at high risk (N15%) of CVD

Polypill vs. usual care

24 months

Castellano JM et al., 2014 [33] Selak V et al., 2014 [34]

FOCUS phase II

Randomized, open-label, active-controlled, piggyback, parallel Randomized, open label

695 post-MI patients

Polypill vs. usual care

9 months

513 patients at high risk (N15%) of CVD

Polypill vs. usual care

Minimum 12 months

Lafeber M et al., 2015 [39]

TEMPUS

Randomized, open, blinded end-point, three-period, crossover

78 patients with established CVD

Morning polypill vs. evening polypill vs. usual care

3–6 weeks per treatment period

Patel A et al., 2015 [35]

Kanyini-GAP Randomized, open-label

623 patients with or at high risk (N15%) of CVD

Polypill vs. usual care

34 months

21 patients with untreated hypertension

Polypill (quadpill) vs. placebo

4 weeks

PILL

IMPACT

Chow CK et al., – 2017 [40]

Randomized, placebo-controlled, double-blind, crossover

morning, in the evening or to the use of single agents taken at different times. Results demonstrated that the polypill-based therapy was associated with an increased adherence; furthermore, patients rated the willingness to continue treatment greater when using the polypill than when using the individual agents. Overall the treatment with the polypill was preferred by 92% of the study participants [39]. Recently, 21 patients with untreated hypertension were enrolled in a randomized placebo-controlled double-blind crossover trial of a quadpill, a single capsule containing four BP-lowering drugs each at quarter-dose (irbesartan 37,5 mg, amlodipine 1,25 mg, hydrochlorothiazide 6,25 mg, and atenolol 12,5 mg) [40]. After 12 months of follow-up, 18 (100%) of 18 patients in quadpill group achieved office blood pressure b 140/90 mm Hg, compared with six (33%) of 18 participants in placebo group (p = 0,0013). Authors also conducted a systematic review of 36 quarter-dose trials (n = 4721 participants), in which quarter-dose BP-lowering drugs reduced systolic and diastolic BP by 4.7 mm Hg and 2.4 mm Hg, respectively. Regarding to safety aspects, the aforementioned studies showed that the most frequent adverse events associated with the polypill were the same as those observed with the single agents taken alone [41]. In conclusion, respect to placebo-controlled trials [27,42], the studies comparing polypill therapy to usual care showed that the polypill provide at least non-inferior SBP and LDL-C reduction. Nevertheless, a

Tolerability (proportion discontinued randomized therapy), LDL-C and SBP at follow-up Reductions in LDL-C and SBP at 12 weeks Effects on SBP, heart rate, serum lipids, serum and urinary K+ and tolerability at follow-up % of adherent patients (indicated medication taken on 4 of preceding 7 days), LDL-C and SBP at baseline and follow-up % of adherent patients (MAQ and pill count) at follow-up % of adherent patients (self-reported current use of antiplatelet, statin and at least two blood pressure-lowering drugs), LDL-C and SBP at follow-up % of adherent patients (microelectronic monitoring device), LDL-C and SBP on each regime % of adherent patients (indicated medication taken on 4 of preceding 7 days), SBP and total cholesterol at baseline and follow-up Effects on 24-hour systolic blood pressure

trend towards polypill superiority in lowering SBP and LDL-C levels was observed [32–34,39,43]. According to these evidences, an individual patients data metaanalysis of 3140 subjects in six countries, combined data from three trials evaluating polypill in patients with CVD or at high risk [32,34,35], showing that, compared to usual care, participants with the FDC pill had higher adherence to combination treatment (relative risk 1.58; 95% CI 1.32 to 1.90), and a 2.5 mm Hg (95% CI 0.4 to 4.5) lower SBP [44]. 5. Discussion Current antihypertensive strategies are limited because of cumbersome and imperfect cardiovascular risk stratification algorithms to identify individuals at risk in primary prevention, lack of systematic implementation of proven therapies in secondary prevention, high cost and low affordability of therapy [43]. In this complex scenario, different approaches, involving a better adherence to medications, a simplification of treatment strategies and a reduction of economic burden of pharmacological treatments, are needed, and a valid pharmacological approach could be represented by the use of ‘polypill’. Studies herein reviewed demonstrate that the polypill strategy may have important advantages. First of all, the polypill has the capacity to independently increase adherence irrespective of patient circumstances

Please cite this article as: D. Cimmaruta, et al., Polypill, hypertension and medication adherence: The solution strategy?, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.11.075

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(e.g., depression, social support, insurance coverage and treatment complexity) [33]. Furthermore, taking one pill instead of three could be an important first step to improve the efficacy of treatments in cardiovascular prevention, especially in patients at high risk of discontinuation [45]. Lastly, polypill could be a cost-effective option for cardiovascular patients [29], not only in low-income countries, but also in those industrialized countries where pharmacological treatments represent a heavy burden on National Healthcare System [46]. On the other hand, the polypill strategy could be compromised by some methodological and clinical shortcomings. The low sample size observed in several polypill studies leads to an insufficient statistical power, responsible for the apparent lack of significant evidences of polypill benefits in cardiovascular risk reduction compared with standard care. Moreover, polypill is not a suitable option for all patients, since its fixed nature prevent any pharmacological adjustments [41]. For the future, it could be designed a polypill with different doses of the individual drugs, which could solve the problem of the adjustments. However, pharmacological customization should be done with the individual components and then transfer patients to the fixed dose combination containing personalized dosages. Another important issue could be represented by patients candidate to aspirin as primary prevention in cardiovascular therapy, since a large proportion of these patients might have resistance to aspirin. These patients are obviously no suitable for the polypill, due to the complex mechanisms involved in aspirin resistance. Furthermore, the choice of the polypill according to its components has to be done in line with patients' characteristics. In fact, some meta-analyses indicate that ACE inhibitors are superior to ARBs in terms of reduction of all-cause mortality [47,48] whereas these latter could be more useful both in terms of adherence and to reduce mortality in secondary prevention, the clinical condition where polypill has been predominantly investigated. The reduction in blood pressure is a class effect for all RAAS blockers and ARBs remain a valuable option for patients that cannot assume ACE inhibitors for their adverse events; based on these evidences, a risk/benefit assessment should always be performed by physicians prior to consider the option of the polypill. Concerning the dosage, RAAS blockers, ACE inhibitors in particular, showed a dose-dependent effect with a beneficial effect on cardiovascular prevention at their highest dosage [49]. Nevertheless, care has always been taken to only combine drugs within the polypill with complementary mechanisms of action and their antihypertensive use is often synergic, thus exerting the same effect in BP reduction [50]. It is also important to underline that the high doses of RAAS blockers in clinical trial settings was established in order to achieve the highest RAAS inhibition. Nevertheless, a percentage of patients greater than one third for each study did not tolerate high doses, but was able to obtain stable BP levels with a reduced dose, since reduction in BP levels could be influenced by individual factors. In conclusion, the use of polypill could represent a solution strategy in patients affected by hypertension, comorbidities and non-adherence even though further studies, especially in the real-world settings, are needed in order to better understand its role in clinical practice.

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Conflict of interest The authors report no relationships that could be construed as a conflict of interest.

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