Adherence to Treatment in Cardiovascular Diseases

The success of any treatment is primarily determined by the adherence to prescribed treatment. Any deviation from it curtails the clinical benefits. Adherence to a medication regimen is described as the degree to which individuals follow the prescribed instructions for taking medications as directed by their healthcare providers.¹

Adherence is a primary determinant of the effectiveness of treatment.² Good adherence improves the effectiveness of interventions aimed at promoting healthy lifestyles and of the pharmacological-based risk-reduction interventions. There are many hurdles for the patients to continue treatment for chronic diseases for prolonged periods of time. Inadequate adherence to treatment regimens is recognized as a significant obstacle in attaining improved outcomes for patients.

Adherence to prolonged therapy is characterized by the degree to which an individual's actions-such as medication intake, adherence to dietary guidelines, and implementation of lifestyle modifications align with the prescribed recommendations from a healthcare provider.³ The effectiveness of treatment is largely determined by how well individuals adhere to it.⁴

The number of individuals suffering from cardiovascular diseases (CVD) is on rise in our country. These persons must take medication regularly that includes many different preparations such as anti-hypertensives, anti-platelet medication, and cholesterol-lowering agent for several months or years. Since the patient must take many preparations daily, can often fail to take them regularly, demonstrating poor adherence. In this background, the use of a combination pill (polypill) containing lower doses of medications that have proved beneficial in the prevention of cardiovascular disease is of great benefit. Raised levels of blood pressure and raised levels of low-density lipoprotein (LDL) cholesterol have been considered to be two leading risk factors for cardiovascular disease. Pharmacologic measures are utilized to manage these risk factors. It is necessary that persons with high-risk recognized on the basis of prediction algorithms should undergo low-cost interventions with relatively fewer side effects.

In the beginning of this century, the World Health Organization (WHO) and the Wellcome Trust held a meeting of experts to search evidence-based and affordable interventions for non-communicable disease (NCD). A consensus emerged that a fixed-dose combination (FDC) polypill containing aspirin, statin and blood pressure lowering agents will facilitate the patients to adhere to treatment and bring down the cost of the medication.⁵

Wald and Law from the UK, proposed that a polypill containing two or more agents that lower blood pressure, a statin and aspirin could significantly bring down the risk of future heart attacks and strokes.⁶ Since the time of introduction of this concept in 2003, it has been debated about its utility in prevention of CVD.

Clinical studies have been undertaken since two decades on two different forms of polypills. The first variety of polypill contains multiple low-dose medications capable of controlling one of the CVD risk factors such as hypertension or hypercholesterolaemia. Such a pill is an example of ‘single-purpose’ polypill. The second category of polypill combines 3 to 4 pharmaceutical agents, each capable of bringing down one major cardiovascular risk factors. Thus, it is an example of ‘multi-purpose’ or ‘cardiovascular’ polypill.

Following analysis of various results from diverse clinical trials and meta-analyses, Wald and collaborators concluded that administering a 'cardiovascular' polypill to individuals aged 50 and above could reduce the incidence of cardiovascular disease by over 80%. The studies showed that such a therapy provided better adherence, better control of risk factors and improved quality of life among persons who used polypill as compared to usual care.⁷

Multi-purpose polypill or cardiovascular polypill contains many pharmaceutical agents, each capable of lowering one of the major cardiovascular risk factors. On the contrary, the ‘single-purpose polypill’ or ‘low fixed-dose combination pill’ combines multiple low-dose medications to control only one risk factor such as hypertension, hyperglycaemia, or hypercholesterolaemia. Such pills came into use to improve safety profile, to improve personal medication adherence and to enhance treatment efficacy.

Hypertension forms the leading cause of cardiovascular disease. Nearly 50% of global burden of CVD is found in Asian countries, among persons belonging to lower socio-economic group.⁸

In a randomized, double-blind controlled trial referred to as the Indian Polycap Study, 548 patients with previous Coronary artery disease (CAD) or diabetes received single dose polypill plus placebo or two polypill capsules for a period of eight weeks and results showed better reduction of blood pressure and LDL cholesterol with the use of polypill. The polypill contained atenolol, hydrochlorothiazide, ramipril, simvastatin and aspirin.⁹

In a meta-analysis of 15 studies comprising 32,331 patients, Gupta and colleagues found a marked improvement in adherence to FDC (Fixed-Dose Combination) of antihypertensive agents compared with free-drug combinations.¹⁰

The Indian Polycap Study conducted a randomized, double-blind, controlled trial with individuals aged 45 to 80 years, who had at least one additional cardiovascular risk factor, to assess the effectiveness and safety of Polycap compared to its individual components. The medication included a fixed dose combination containing five drugs (an anti-platelet drug; three blood pressure lowering agents, a beta blocker, an ACE inhibitor, a diuretic and a statin). The study revealed that the Polycap formulation has the potential to significantly alleviate multiple risk factors associated with cardiovascular disease.⁹

Different studies carried out in different regions of the world have shown that polypill helps in bringing down the blood pressure and cholesterol levels. It helps in CVD prevention with improvement in adherence to medication. The results have validated that individuals using the polypill demonstrated improved adherence, as well as equivalent or superior control of risk factors and quality of life.¹¹

The first large clinical trial (TIPS-3), conducted at 86 centres in nine countries, examined usefulness of Polycap in the reduction of blood pressure and cholesterol. It proved to be useful in the primary prevention of CVD in individuals at increased risk.¹² There was an initial hypothesis that individuals without clinical cardiovascular disease (CVD) but at an elevated CVD risk could achieve a 50% to 60% reduction in CVD risk by utilizing a single "polypill" combining multiple blood-pressure medications and a statin, with or without aspirin. The findings from the TIPS-3 study have provided valuable insights into the suitability of FDC therapy as a strategy for global CVD prevention.

A randomized, controlled trial was carried out by Munoz and colleagues in Alabama, the US, on 303 adults without any cardiovascular disease. They divided the participants into two groups as polypill group and usual-care group. Polypill group received atorovastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg). During the study period of one year, greater reductions in systolic blood pressure and LDL Cholesterol were noted in polypill group than usual care group.¹³

Yusuf and colleagues carried out a study on 5713 persons over a period of 4.6 years. Participants without cardiovascular disease and with an elevated INTERHEART Risk Score were randomly allocated to receive a daily polypill (comprising 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or a placebo. Additionally, they were assigned to take a daily dose of aspirin (75 mg) or a placebo, as well as a monthly dose of vitamin D or a placebo.14 The findings indicated that among individuals without pre-existing cardiovascular disease but with an intermediate cardiovascular risk, the combined therapy of a polypill along with aspirin resulted in a reduced occurrence of cardiovascular events compared to a placebo.¹⁴

Kandil and colleagues evaluated the effect of polypills on the primary prevention of cardiovascular (CV) events using data from eight trials having a total of 20653 patients and found a significant reduction in the total number of fatal and non-fatal cardiovascular events among those receiving polypill.¹⁵ They found it beneficial in the five-year follow-up period. Moreover,there was a significant decrease in the 10-year predicted cardiovascular risk within the polypill group.

Phase 3, randomized, controlled multinational Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial, included 2499 patients who had myocardial infarction within the previous six months. They were given a polypill- or usual care over a period of three years.¹⁶ The polypill treatment included aspirin 100 mg, ramipril 2.5, 5, or 10 mg, and atorvastatin 20 or 40 mg. The administration of polypill treatment demonstrated a significantly reduced risk of major adverse cardiovascular events compared to standard care. Utilizing a cardiovascular polypill demonstrated its capability to replace various individual cardiovascular medications, affirming its potential as a crucial component of an efficient secondary prevention strategy. Use of a polypill improves accessibility to treatment, thus reducing the risk of recurrent disease and cardiovascular death.

A meta-analysis was carried out on the results of six studies with a total sample of 13,139 (6577 in polypill group and 6562 in the control group) to assess the impact of polypill on medication adherence and clinical outcomes in patients with or at high risk of CVD. Memon and colleagues found that medication adherence was significantly higher in patients receiving polypill compared to the control group. There was marked decrease in the occurrence of cardiovascular events in the polypill group.¹⁷ The meta-analysis revealed a substantial impact of polypills on medication adherence, indicating that they could decrease the occurrence of cardiovascular events in patients with or at a high risk of cardiovascular disease.

Thus research carried out in different parts of the globe has shown polypills to be an inexpensive, effective way to bring down the risk of cardiac problems by almost 40%.

The World Health Organization's Essential Medicines List comprises medications deemed essential for any healthcare system, representing the minimum requirements. Updated biennially, it aids in prioritizing accessible and cost-effective medicines.

There is a vision that the cardiovascular polypill could play a crucial role in global strategies aimed at preventing cardiovascular events in individuals with a history of myocardial infarction and those undergoing treatment with distinct mono-components.

Ensuring compliance with treatment regimens after experiencing an acute myocardial infarction is crucial for achieving effective secondary prevention. The cardiovascular polypill, incorporating three baseline treatments for these patients, has demonstrated its efficacy, attributed to heightened adherence.

The cardiovascular polypill, which includes acetylsalicylic acid, ramipril, and atorvastatin, created by the Spanish Centro Nacional de Investigaciones Cardiovasculares (CNIC) in collaboration with the Ferrer pharmaceutical company, has been added to the World Health Organization's Essential Medicines List. The polypill has demonstrated effectiveness in preventing subsequent adverse cardiovascular events in individuals with a history of a previous heart attack. Further it showed reduction in cardiovascular mortality by 33% in them.18 The concept of the polypill has gained acceptance in the past decade. Numerous trials have indicated enhanced adherence and a decrease in the cardiovascular risk associated with high blood pressure and elevated LDL cholesterol.

Conflict of interest

Nil