Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) scientific statement on the simplification of the drug regimen for secondary cardiovascular prevention.

The issue of suboptimal drug regimen adherence in secondary cardiovascular prevention presents a significant barrier to improving patient outcomes. To address this, the utilization of drug combinations, specifically single pill combinations (SPCs) and polypills, was proposed as a strategy to simplify treatment regimens. This approach aims to enhance treatment accessibility, affordability, and adherence, thereby reducing healthcare costs and improving patient health. The document is an Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) scientific statement on simplifying drug regimens for secondary cardiovascular prevention. It discusses the underuse of treatments despite available, effective, and accessible options, highlighting a significant gap in secondary prevention across different socio-economic statuses and countries. The statement explores barriers to implementing evidence-based treatments, including patient, healthcare provider, and system-related challenges. The paper also reviews international guidelines, the role of SPCs and polypills in clinical practice, and their economic impact, advocating for their use in secondary prevention to improve patient outcomes and adherence.

Polypill Strategy in Secondary Cardiovascular Prevention.

PURPOSE OF REVIEW: The polypill strategy, originally developed to improve medication adherence, has demonstrated efficacy in improving baseline systolic blood pressures and cholesterol levels in multiple clinical trials. However, the long-term clinical impact of improved major cardiovascular events (MACE) outcomes by the polypill remains uncertain. RECENT FINDINGS: Recent trials with long-term follow-up, which included minority groups and people with low socioeconomic status, have shown non-inferiority with no difference in adverse effects rates for the secondary prevention of MACE. Although the polypill strategy was initially introduced to improve adherence to guideline-directed medical therapy (GDMT) for cardiovascular complications, the strategy has surpassed standard medical treatment for secondary prevention of MACE outcomes. Studies also showed improved medication compliance in underserved populations.

Fixed Combination for the Treatment of Dyslipidaemia.

PURPOSE OF REVIEW: It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals. RECENT FINDINGS: The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.

Pharmacotherapy Decision Aids for the American Heart Association 2021 Statement on Management of Stage 1 Hypertension.

PURPOSE OF REVIEW: This is a pragmatic decision aid for initiating pharmacotherapy for stage 1 hypertension. RECENT FINDINGS: If a stage 1 patient presents with clinical signs of fluid retention, then a diuretic should be the primary agent. However, if the patient is normovolemic, then a vasodilator should be the primary agent. If targeted blood pressure is not achieved with the primary agent, then the choices are dose escalation or the addition of a second drug. For stage 1, the addition of secondary agents is preferred. This approach includes the polypill (a single pill with multiple low-dose antihypertensive agents). The positives are the polypill lessens the need to make decisions associated with up-titration and the low doses mitigate adverse side effects. The polypill targets several concurrent mechanisms to counteract hypertension. For stage 1, the goal should be to lower blood pressure with a simple regiment which minimizes adverse side affects.

Polypill and Combination Therapy: Blood Pressure and Cardiovascular Risk Reduction.

PURPOSE OF REVIEW: The number of medications prescribed to patients has been progressively increasing, primarily driven by cardioprotective medications. The advent of pharmaceutical 3D printing technology holds the promise of reducing the burden of multiple pills by combining various medications with different release mechanisms into a single tablet. This development encourages a comprehensive review of the evidence supporting the use of combination pills. RECENT FINDINGS: Recent randomized studies have shown higher BP control rates in quadpill groups than in monotherapy groups and improved 6-month BP control rates with a low-dose triple fixed-dose combination (FDC) medication compared to usual care. Recent randomized controlled trials also support FDC use for primary and secondary prevention of cardiovascular disease. Three-dimensional printing technologies such as powder-based (PB) 3D printing, fused deposition modeling (FDM) 3D printing, and semisolid extrusion (EXT) 3D printing are examples of promising technologies that could be utilized to combine multiple medications with different release mechanisms into a single tablet. FDC therapy can provide patients with combination regimens with a reduced pill burden, which promotes improved adherence and efficacy. Recent randomized trials have shown that FDC can be used for primary and secondary prevention of cardiovascular disease with no significant difference in adverse events. Multidisciplinary approaches should be implemented to enhance long-term adherence, and further research on establishing affordable and effective initial dual antihypertensive therapy options is necessary. Pharmaceutical 3D printing technology may play an important role in enhancing the flexibility, affordability, and feasibility of clinical FDC utilization.

Polypill for prevention of cardiovascular diseases with focus on non-alcoholic steatohepatitis: the PolyIran-Liver trial.

AIMS: Individuals with non-alcoholic steatohepatitis or elevated liver enzymes have increased cardiovascular mortality but are often excluded from prevention trials. We investigated the effectiveness of fixed-dose combination therapy for the prevention of major cardiovascular events (MCVE) among individuals with and without presumed non-alcoholic steatohepatitis (pNASH). METHODS AND RESULTS: Two thousand four hundred participants over 50 were randomized into the intervention and control groups. Consent was obtained post-randomization. Consenting participants in the intervention group were given a pill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill). Participants were followed for 5 years. Presumed non-alcoholic steatohepatitis was diagnosed by ultrasonography and elevated liver enzymes. The primary outcome was MCVE. ClinicalTrials.gov: NCT01245608. Among the originally randomized population, 138 of 1249 in the intervention group (11.0%) and 137 of 1017 controls (13.5%) had MCVE during the 5-year follow-up [unadjusted risk ratio (RR) 0.83, 95% confidence interval (CI) 0.66-1.03]. Of the 1508 participants who consented to additional measurements and treatment, 63 of 787 (8.0%) intervention group participants and 86 of 721 (11.9%) controls had MCVE (adjusted RR 0.61, 95% CI 0.44-0.83). Although the adjusted relative risk of MCVE in participants with pNASH (0.35, 95% CI 0.17-0.74) was under half that for participants without pNASH (0.73, 95% CI 0.49-1.00), the difference did not reach statistical significance. There was no change in liver enzymes in participants taking polypill but among those with pNASH, there was a significant decrease after 60 months of follow-up (intragroup -12.0 IU/L, 95% CI -14.2 to -9.6). CONCLUSION: Among patients consenting to receive fixed-dose combination therapy, polypill is safe and effective for the prevention of MCVE, even among participants with fatty liver and increased liver enzymes.

Polypharmacy and Cardiovascular Diseases: Consideration for Older Adults and Women.

PURPOSE OF REVIEW: The intent of this review is to provide an update in polypharmacy in older adults and women with a focus on common determinants and strategies to mitigate polypharmacy. RECENT FINDINGS: Polypharmacy is becoming a critical focus in the management of cardiovascular diseases. It may emerge unintentionally while managing multimorbidity in older adults or in the vulnerable subgroup of patients, such as pregnant and lactating females. Clinicians should utilize several approaches such as deprescribing, sex-specific risk assessment, and encouraging healthy lifestyle to minimize inappropriate and unnecessary use of medications. A shared decision-making model along with coordination and collaboration among healthcare providers should be utilized in the selection and management of pharmacotherapies.

Safety and efficacy of a cardiovascular polypill in people at high and very high risk without a previous cardiovascular event: the international VULCANO randomised clinical trial.

BACKGROUND: Cardiovascular (CV) polypills are a useful baseline treatment to prevent CV diseases by combining different drug classes in a single pill to simultaneously target more than one risk factor. The aim of the present trial was to determine whether the treatment with the CNIC-polypill was at least non-inferior to usual care in terms of low-density lipoprotein cholesterol (LDL-c) and systolic BP (SBP) values in subjects at high or very high risk without a previous CV event. METHODS: The VULCANO was an international, multicentre open-label trial involving 492 participants recruited from hospital clinics or primary care centres. Patients were randomised to the CNIC-polypill -containing aspirin, atorvastatin, and ramipril- or usual care. The primary outcome was the comparison of the mean change in LDL-c and SBP values after 16 weeks of treatment between treatment groups. RESULTS: The upper confidence limit of the mean change in LDL-c between treatments was below the prespecified margin (10 mg/dL) and above zero, and non-inferiority and superiority of the CNIC-polypill (p = 0.0001) was reached. There were no significant differences in SBP between groups. However, the upper confidence limit crossed the prespecified non-inferiority margin of 3 mm Hg. Significant differences favoured the CNIC-polypill in reducing total cholesterol (p = 0.0004) and non-high-density lipoprotein cholesterol levels (p = 0.0017). There were no reports of major bleeding episodes. The frequency of non-serious gastrointestinal disorders was more frequent in the CNIC-polypill arm. CONCLUSION: The switch from conventional treatment to the CNIC-polypill approach was safe and appears a reasonable strategy to control risk factors and prevent CVD. Trial registration This trial was registered in the EU Clinical Trials Register (EudraCT) the 20th February 2017 (register number 2016-004015-13; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-004015-13 ).

Polypills in Cardiovascular Disease Prevention: Mass-Strategy Approach, Precision Medicine, or an Essential Intertwine Between Them?

PURPOSE OF REVIEW: This review considers the framework of high-risk vs. population approaches as proposed in the Rose's axiom within the context of cardiovascular diseases, including its benefits and limitations. We also contextualize the use of precision medicine in primary prevention therapy and contrast that with population approach. RECENT FINDINGS: Although the high-risk strategy aims at individualized care, the complexity of pharmacologic regimens and other limitations reduces its real-life impact. On the other hand, broad population strategies include treatment of a substantial number of low-risk individuals who are unlikely to benefit from treatment. The use of additional strategies to identify those low-risk individuals, instead of targeting at identifying the high-risk population, is and alternative strategy to be considered. Evidence of the potential use of coronary artery calcium score and polypills for this strategy is discussed. A more targeted population approach to primary prevention in cardiovascular diseases with the use of polypills and coronary artery calcium score might be considered in a structured mass-strategy approach to risk reduction.

Highlights from Studies Presented at the American Heart Association Scientific Session 2020: Navigating New Roads in Prevention.

PURPOSE OF THE REVIEW: This review highlights late-breaking science presented at the American Heart Association Scientific Session 2020 that demonstrated advancements in preventative cardiology and introduced novel treatment approaches for the management of chronic kidney disease, type 2 diabetes, and/or heart failure. RECENT FINDINGS: The studies reviewed include clinical trials that assessed the use of omecamtiv in the treatment of heart failure with reduced heart failure (GALACTIC-HF); effects of sotagliflozin in patients with diabetes and recent heart failure exacerbation; cardiovascular outcomes with the use of omega-3 carboxylic acids in patients with high vascular risk and atherogenic dyslipidemia (STRENGTH) and omega-3 fatty acids in elderly patients with recent myocardial infarction (OMEMI); efficacy and safety of evinacumab in patients with refractory hypercholesterolemia; and the use of coronary computed tomography angiography for the assessment of suspected acute coronary syndrome. In addition, we review the results of the International Polycaps Study (TIPS-3) on the use of a polypill for the primary prevention of cardiovascular disease in intermediate-risk people. Finally, we discuss the SAMSON trial-a three-arm-N-of-1 trial-to identify the root cause of the symptoms contributing to patient nonadherence to statin therapy. The studies presented at the American Heart Association Scientific Session 2020 represent remarkable contributions in the field of cardiovascular disease and prevention.

The Attitude towards Polypills Questionnaire (APPQ): a phase I-III development and validation study in patients with cerebrovascular disease.

BACKGROUND AND PURPOSE: The polypill approach has been proposed to reduce patients' pill burden, increase medication adherence and lower stroke incidence. However, little is known about patients' attitudes towards polypills for cerebrovascular medication. METHODS: Based on the European Organization for Research and Treatment of Cancer Quality of Life Group questionnaire development guidelines, a questionnaire to measure patients' attitudes towards polypills for the secondary prevention of stroke (phase I-III) was developed. In phase I, issues were generated via literature review and interviews with patients and healthcare professionals. The issues were operationalized into items in phase II. In phase III the questionnaire was validated in a large single-centre sample, and test-retest and internal validity were evaluated. RESULTS: In phase I, 34 relevant issues were identified through literature search and interviews. Pre-testing the questionnaire indicated high applicability and comprehensibility. The final Attitudes towards Polypills Questionnaire was tested in N = 260 patients and showed a two-factor structure. The factors were labelled 'concerns' and 'benefits'. The scales showed acceptable and good internal validity (concerns, Cronbach's α = 0.85; benefits, α = 0.93), but the scales' test-retest validity was ambiguous. On a 0 to 3 rating scale, concerns were rated lower than benefits (mean 1.07, SD 0.69 vs. mean 1.87, SD 0.89). CONCLUSIONS: The Attitudes towards Polypills Questionnaire showed high comprehensibility and content validity to assess German language patients' attitudes towards a polypill medication. Our data and questionnaire may aid the implementation of polypill treatments in clinical practice and can be used in the design of future clinical trials on polypill therapy. Further validation of the questionnaire is advised.

Reconsidering the Polypill for Management of Cardiovascular Risk Factors in Underserved Patients.

PURPOSE OF REVIEW: The recent publication of "Polypill for Cardiovascular Disease Prevention in an Underserved Population" study prompts a thoughtful review of known care disparities in cardiovascular disease management in underserved patients. A polypill approach as a population health solution to this complex problem should also be reviewed. RECENT FINDINGS: Muñoz and colleagues open-label, randomized controlled trial of polypill vs. usual care was undertaken in minority patients at a federally qualified health center. The polypill, containing atorvastatin, amlodipine, losartan, and hydrochlorothiazide resulted in statistically significant improvements in systolic blood pressure and low-density lipoprotein levels (p = 0.003 and p < 0.001, respectively). The significant results of this study demonstrate the ability of a polypill approach to safely lower blood pressure, lipids, and thus estimated 10-year risk of CVD and are consistent with findings observed in previous literature. Uniquely, findings in a largely non-Hispanic Black patient population, offer an opportunity to examine this approach to combat important disparities in care in an underserved U.S. community. Further outcomes-based studies are warranted to explore the validity of these results and long-term safety of polypill treatment and are likely necessary prior to FDA approval and availability of a polypill product.

3D Printing as a Promising Tool in Personalized Medicine.

Personalized medicine has the potential to revolutionize the healthcare sector, its goal being to tailor medication to a particular individual by taking into consideration the physiology, drug response, and genetic profile of that individual. There are many technologies emerging to cause this paradigm shift from the conventional "one size fits all" to personalized medicine, the major one being three-dimensional (3D) printing. 3D printing involves the establishment of a three-dimensional object, in a layer upon layer manner using various computer software. 3D printing can be used to construct a wide variety of pharmaceutical dosage forms varying in shape, release profile, and drug combination. The major technological platforms of 3D printing researched on in the pharmaceutical sector include inkjet printing, binder jetting, fused filament fabrication, selective laser sintering, stereolithography, and pressure-assisted microsyringe. A possible future application of this technology could be in a clinical setting, where prescriptions could be dispensed based on individual needs. This manuscript points out the various 3D printing technologies and their applications in research for fabricating pharmaceutical products, along with their pros and cons. It also presents its potential in personalized medicine by individualizing the dose, release profiles, and incorporating multiple drugs in a polypill. An insight on how it tends to various populations is also provided. An approach of how it can be used in a clinical setting is also highlighted. Also, various challenges faced are pointed out, which must be overcome for the success of this technology in personalized medicine.

Low-Dose Combination Therapy for Initial Treatment of Hypertension.

PURPOSE OF REVIEW: To summarise the advances that have been made from 2017 in dual, triple, and quadruple low-dose combination therapy for treating high blood pressure. RECENT FINDINGS: Many people require multiple blood pressure lowering medicines to achieve target blood pressures, and initiating treatment with combination blood pressure lowering therapy is being increasingly investigated and recommended. Low-dose combinations of blood pressure lowering provide more effective blood pressure lowering, with fewer adverse events. Recent advances include listing of four dual combinations on the WHO Essential Medicines List, completion of a triple half-dose combination trial, and a pilot of quadruple quarter-dose combination, and recent cardiovascular polypill trials have included two blood pressure lowering medicines at low dose. These trials all demonstrated improvements in achieving blood pressure targets with low-dose combination therapy. Low-dose combination therapy is a promising option for initial treatment of hypertension that appears to be safe and effective. Larger trials of triple and quadruple low-dose combination therapy in multiple locations are underway and should provide stronger evidence of efficacy as well as information on the side effect profile.

Polypill Trials for Stroke Prevention-Main Results, Critical Appraisal, and Implications for US Population.

PURPOSE OF REVIEW: The polypill, referring to a variety of combinations of low-cost cardiovascular and stroke preventive medications combined in a single tablet, has been evaluated as a population-based approach for cardiovascular disease prevention in several trials. This review summarizes the scope of the problem, main trial results, and their potential applicability to the US population. RECENT FINDINGS: Initial trials demonstrated the efficacy of the polypill approach. The most recent, the PolyIran study, showed the effectiveness of one form of a polypill for cardiovascular disease prevention, high medication adherence, and low adverse event rates. None of published polypill trials focused on stroke as the primary outcome and most were conducted in developing countries, limiting generalization to the US population. A US-based randomized trial with stroke as the primary outcome is needed to assess the usefulness of this approach for stroke prevention in the USA.

Efficacy and toxicity of antihypertensive pharmacotherapy relative to effective dose 50.

Antihypertensive drugs have usually been approved at doses near the top of their respective dose-response curves. Efficacy plateaus but adverse drug reactions (ADRs), such as falls, cerebral or renal ischaemia, increase as dose is increased, especially in older patients with comorbidities. ADRs reduce adherence and may be difficult to ascertain reliably. Higher doses have generally not been shown to reduce total mortality, which provides a summary of efficacy and safety. Weight loss and other lifestyle measures are essential and may be sufficient treatment in many young and low risk patients. Most antihypertensive drug lower systolic blood pressure by around 10 mmHg, which reduces stroke and heart failure by about a quarter. Clinical trials have not been designed to demonstrate specific blood pressure treatment thresholds and targets, which are mostly extrapolated from epidemiology. Mean population oral effective dose 50 may be the most appropriate dose at which to commence antihypertensive drugs. The dose can then be titrated up if greater efficacy is demonstrated, or lowered if ADRs develop. Lower dose combination therapy may best balance benefit and harms with fewer ADRs and additive, potentially synergistic, efficacy.

[Management of different cardiovascular risk factors with a combination tablet (polypill)]. / Management verschiedener kardiovaskulärer Risikofaktoren mit einem Kombinationspräparat ("Polypill").

BACKGROUND: The multifactorial origin of cardiovascular diseases has led to polypharmacy in primary and secondary prophylaxis with evidence-based medications, such as statins, antihypertensive drugs and platelet aggregation inhibitors. The number of prescribed drugs correlates inversely to adherence and can lead to treatment failure. Fixed-dose combination drugs (polypills) could increase the medication adherence of patients, reduce risks and prevent cardiovascular events. METHODS: This review is based on publications that were retrieved from Medline (via PubMed) and The Cochrane Library. The clinical database ClinicalTrials.gov. was also considered. RESULTS: In the studies on primary prevention conducted to date, fixed-dose combinations showed a superior control of risk factors, e.g. hypertension and low-density lipoprotein (LDL) cholesterol compared to placebo and at least non-inferiority compared to usual care. In secondary prevention, the effect of the polypill is mostly on the reduction of blood pressure and LDL cholesterol in non-adherent patients; however, evidence that fixed-drug combinations reduce cardiovascular morbidity and mortality compared to standard therapy is lacking. CONCLUSION: The polypill can be considered as an alternative to polypharmacy after a risk-benefit assessment, especially in non-adherent patients. Ongoing studies are investigating the effect of the polypill on cardiovascular events. Current polypills are limited by the lack of sufficient dosages of the individual components to avoid overtreatment and undertreatment at the individual treatment level.

Strengths and Limitations of Using the Polypill in Cardiovascular Prevention.

PURPOSE OF REVIEW: Polypill and its role in cardiovascular disease (CVD) prevention has been extensively discussed and debated since the inception of the concept in 2003. This article reviews the subsequent accumulated research in this area. RECENT FINDINGS: Several short and intermediate to long-term studies with different brands of polypills have analysed the impact of polypill in phase II and III trials. The strengths of polypill that have emerged include better adherence, equivalent or better risk factor control and quality of life among polypill users as compared to usual care. The lurking limitations include difficulty with dose adjustment to targets, fear of mass medicalisation and low acceptability among physicians. The current literature supports polypill use in reducing blood pressure and cholesterol levels for CVD prevention with improvement in adherence to medication. However, the long-term outcome of polypill on CVD events and mortality are unavailable and are currently being studied in clinical trials.

[Lisinopril, Amlodipine, Rosuvastatin as a Novel Fixed Combination in the Fight Against Cardiovascular Disease].

The prevalence of multicomponent therapy in treatment of cardiovascular diseases makes fixed combinations of drugs very useful. The fixed combination of rosuvastatin with ACE inhibitor lisinopril and calcium antagonist amlodipine allows to control effectively two main cardiovascular risk factors: hypercholesterolemia and arterial hypertension. The efficacy of each of the components and their combined administration in primary and secondary prevention of cardiovascular disease has been demonstrated in clinical studies. The convenience of several drugs combination in a single tablet increases adherence to therapy facilitating regular intake of all treatment components and reliably reducing the risk of cardiovascular complications.