It was on a visit to New York in 1999, recovering from a recent illness, that Nicholas Wald first considered the idea of a ‘polypill’ for cardiovascular disease (CVD).
It made perfect sense to Wald, who was director of the Wolfson Institute of Preventive Medicine in London at the time: combine the complementary effects of statins, blood pressure-lowering medicines, aspirin and folic acid to prevent a first heart attack or stroke.
“Such combinations of medicines were frequently prescribed for people who had had a heart attack to reduce their risk of having a second one,” he says. “The modes of action were largely independent and there was no practical threshold below which lowering serum cholesterol and blood pressure did not reduce the risk of cardiovascular disease.”
Wald predicted that around 80% of heart attacks and strokes could be averted if his proposed polypill was taken by everyone aged 55 years and over, and everyone with existing CVD
At around the same time, epidemiologists were debating the value of a fixed-dose combination (FDC) pill for secondary prevention of CVD, particularly in low and middle-income countries. The rationale for FDCs was becoming well established in communicable diseases, such as tuberculosis, malaria and HIV/AIDS, where reduction in pill burden, simplification of drug regimens and standardisation of dosing had contributed to improved treatment coverage and control rates (see Box 1)
Box 1: Use of fixed-dose combination pills in other diseases
Use of fixed-dose combination (FDC) pills for some diseases, such as HIV, tuberculosis, malaria and hepatitis C, is well established.
FDCs for tuberculosis have been manufactured since the 1980s. The first FDC for HIV emerged in the mid-1990s, with Combivir (zidovudine and lamivudine; GSK) approved by the US Food and Drug Administration in 1997. Artemether-lumefantrine (Coartem; Novartis) was the first fixed-dose antimalarial combination containing an artemisinin derivative and has been approved for use since 1999. Several FDCs for hepatitis C treatment have emerged in recent years; an FDC of velpatasvir and sofosbuvir (Epclusa; Gilead), the first single treatment licensed for all hepatitis C genotypes, was approved in Europe in 2016.
For these diseases, FDCs have become mainstays of treatment and are recommended and endorsed as essential medicines by the World Health Organization, ensuring their widespread uptake.
At a meeting convened by the World Health Organization (WHO) and the Wellcome Trust in August 2001, experts agreed that a combination pill might go some way to address the adherence and access issues associated with multiple drug treatment in CVD
A programme of work to evaluate such an approach over the next five years was outlined, with the expectation that FDC therapy — if shown to be effective and cost effective for secondary prevention of CVD — would be integrated into existing healthcare systems.
Nearly two decades on and progress towards these goals has been glacially slow.
Barriers to development
According to Mark Huffman, a cardiologist and researcher in preventative medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois, barriers to the development and uptake of polypills — which are generally defined as single FDCs containing at least one blood pressure-lowering drug and one lipid-lowering drug with or without aspirin — have been multifactorial.
He says the mass treatment approach proposed by Wald has held polypills back. “That led to a lot of debate and discussion,” he explains, creating what he describes as a “legacy barrier” and opposition to the concept of FDCs for CVD, in contrast to other therapeutic areas.
Other blocks include low levels of investment by pharmaceutical companies, uncertainty associated with intellectual property, and manufacturing and regulatory issues.
JosÃ© MarÃa Castellano is clinical trials coordinator at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid. In 2007/2008, the CNIC partnered with Ferrer, a privately-owned pharmaceutical company, to develop the polypill concept after failing to convince any of the major drug companies to jump on board. “They declined, probably because they didn’t see enough margins on the return of the product,” he says.
“It’s not a high-profit game,” agrees Ruth Webster, a researcher at the George Institute for Global Health based in Sydney, Australia.
You can’t charge much; people won’t pay for it; you’re going to have to get high-volume, low-margin sales to make any kind of profit
The drugs contained in most polypills are off patent, so products are unlikely to attract a premium. “You can’t charge much; people won’t pay for it,” says Webster. “You’re going to have to get high-volume, low-margin sales to make any kind of profit.”
Intellectual property is more likely to relate to the formulation or combination of treatments used. This makes the patents hard to defend, says Webster. “There’s so many different blood pressure-lowering medications, so many different cholesterol-lowering medications. Can you patent any combination of all of them and then defend it successfully?”
Accepted thinking on which components should make up the polypill has also changed over time — the polypill proposed in 2003 by Wald and his colleague Malcolm Law included folate, which is no longer recommended.
“Even the provision of aspirin for the primary prevention of CVD has waning support in the context of the risk to benefit balance,” says Huffman.
In addition, questions remain over who the target population should be (even when discounting the mass treatment approach) — individuals with established heart disease (secondary prevention), or those at high risk of developing heart disease (primary prevention)?
Then, there are the many potential combinations of drugs, with different clinicians having different preferences. “There’s not one perfect combination,” says Huffman. “Perhaps there was a challenge in having perfect be the enemy of good.”
The CNIC-polypill contains aspirin, the ACE-inhibitor ramipril and either atorvastatin or, in Latin America, simvastatin. The multi-layered formulation, housed in a capsule, was developed using a technology patented by Ferrer. The technology successfully avoids the physico-chemical incompatibilities of the individual components and conserves their biopharmaceutical and pharmacokinetic properties
. It wasn’t just a case of mixing the components together — scientists at Ferrer started work on the polypill in 2007, with the first pill launched in 2014.
“It is very, very complex … to make sure that all the ingredients in the polypill are bioequivalent to their generic counterparts,” says Castellano. “The people at Ferrer … did an outstanding job.”
Some countries don’t allow regulatory approval of FDCs altogether.; others lack protocols, so even though they see the need … they turn down the regulatory approval
Regulatory hurdles differ by country, adds Castellano. “Some countries don’t allow regulatory approval of FDCs altogether. Others lack protocols, so even though they see the need … they turn down the regulatory approval.”
Where regulators are receptive to FDCs, Ferrer has not had to provide reams of clinical trial data. “They’re not really looking for hard outcome trials because each generic drug has vast data behind it,” says Castellano. “They are only looking for proof that you can make it and that it is bioequivalent and retains the [pharmacokinetic and pharmacodynamic] properties of the generics.”
Several polypills for CVD are available or in development (see Box 2). A handful have marketing approval in India only, and a couple more are available in Iran. Ferrer’s is the only polypill to have gained extensive market approval and is commercialised in 31 countries across Europe, and Central and Latin America.
Box 2: Polypills
With marketing approval:
- Atamra CV kit (atorvastatin, ramipril, clopidogrel); Amra Remedies
- CV-Pill kit (ramipril, metoprolol, atorvastatin, aspirin); Torrent Pharmaceuticals
- Heart Pill (ramipril, atorvastatin, aspirin); Excella Pharma
- Polycap (aspirin, ramipril, hydrochlorothiazide, atenolol, simvastatin); Cadila Pharmaceuticals
- Polypill-E (aspirin, atorvastatin, hydrochlorothiazide, enalapril); Alborz Darou Pharmaceuticals
- Polypill-V (aspirin, atorvastatin, hydrochlorothiazide, valsartan); Alborz Darou Pharmaceuticals
- Ramitorva (aspirin, ramipril, atorvastatin); Zydus Cadila Healthcare
- RIL–AA (ramipril, atorvastatin, aspirin); East West Pharma
- Starpill (aspirin, losartan, atenolol, atorvastatin); Cipla
- Trinomia* (aspirin, ramipril, atorvastatin or simvastatin); Ferrer
- Triveram (perindopril, amlodipine, atorvastatin); Servier
- ZYCAD-4 kit (ramipril, metoprolol, atorvastatin, aspirin); Zydus Cadila Healthcare
- GSK3074477 (amlodipine, rosuvastatin); GlaxoSmithKline
- Livalo (pitavastatin, valsartan); JW Pharmaceutical
- Polytorva A (ramipril, atorvastatin); USV
- Polytorva B (aspirin, ramipril, atorvastatin); USV
- Unnamed (valsartan, rosuvastatin); EMS
*Marketed as Iltria in Germany and as Sincronium in Mexico
Despite having marketing approval in more than 40 countries worldwide, uptake of CVD polypills is limited. Barriers include poor physician uptake, a lack of evidence on hard clinical outcomes and an absence of government reimbursement.
Diederick Grobbee, a clinical epidemiologist at the University Medical Center Utrecht, the Netherlands, worked with Webster under the SPACE (single pill to avert cardiovascular events) collaboration, which has conducted trials of a four-component polypill for CVD across Australia, New Zealand and Europe.
As a cardiologist, Grobbee was trained to tailor care to the individual. “We customise and we tweak,” he says, describing this approach as highly personalised and yet highly ineffective on a large scale. “I reason that it’s better to have a whole lot of people treated 80% well than just a few 100% well.”
Cardiologists like to titrate drugs, they like to individualise therapy … and you cannot do that with a polypill
Webster notes that doctors who participate in polypill trials tend to love them, but others are sceptical about widespread use. “Cardiologists like to titrate drugs, they like to individualise therapy … and you cannot do that with a polypill,” she says.
However, Ferrer argues that its polypill does allow for personalised therapy. “There is a need to establish a baseline cardiovascular treatment for patients after a cardiovascular event,” says a spokesperson for the company. “The baseline treatment should include the minimum drugs that a patient should take for the rest of their life after a cardiovascular event.”
Castellano agrees, referring to the polypill as “core treatment”. If a further antihypertensive drug is needed, then one can be added.
However, Huffman emphasises that, in many parts of the world, the greatest barrier to uptake is the limited options of an FDC that clinicians want to use.
“There’s general consensus on the classes of medicines for which there’s benefit, but the specific angiotensin receptor blocker, for example, there’s a whole heap of them.”
On the other hand, Huffman recognises that, from a scalability standpoint, the number of choices may need to be minimised. “That’s what’s allowed combination therapy in HIV or TB and even malaria to be scaled up,” he says. “There’s only so many drugs in those treatment classes.”
Castellano points out that one of the major conceptual barriers to polypills, which have been shown to improve adherence to treatment by 44%, is that doctors do not necessarily see non-adherence as a problem
. However, while doctors are doubling the dose of their patient’s statin to achieve an incremental improvement in LDL-cholesterol reduction, Castellano points out that 50% of patients will drop their medicines six months after the acute event
“As doctors, we don’t spend enough time explaining the urgent need for [our patients] to remain on those medications lifelong,” adds Castellano.
Another potential block to the uptake of polypills relates to concerns that adverse effects associated with one of the polypill’s components could lead to its discontinuation and the loss of all the other components’ benefits.
However, Huffman says this does not seem to be borne out by the available evidence. “Trial data argue against that because of the increased rate of adherence among individuals randomised to FDC therapy.”
Evidence for the effectiveness and cost-effectiveness of polypills comes from more than a dozen clinical trials, involving around 17,000 patients in total,
. Results from early trials have shown that polypills improve adherence, are generally well tolerated, and reduce CVD risk factor levels
Four trials of polypills versus usual care have reported favourable data on acceptability to physicians or patients
. Reported advantages to polypill therapy were ease and convenience, cost-saving benefits and improved safety from simplifying pill regimens
Real-world experience in implementation is mainly derived from the CNIC-Ferrer Polypill project
What has been missing until recently is hard outcomes data, although many polypill enthusiasts argue that there is no need to conduct expensive event trials for polypills — the data are there for the individual components.
“Assuming the bioequivalence is the same, which has been shown … if you’re taking these drugs, then you will get an effect on events the same as if you took them individually,” says Webster.
However, Castellano believes that a lack of outcomes data is one of the reasons why the polypill is not globally implemented. “You can indirectly correlate the impact on mortality — but scientists want hard endpoints.”
To this end, CNIC has embarked on a European trial, funded under the EU’s Horizon 2020 initiative, to test the hypothesis that the polypill is able to reduce major cardiovascular events. The investigators aim to recruit around 3,000 patients from seven European countries — Spain, Italy, France, the Czech Republic, Germany, Poland and Hungary. Results from the trial, known as SECURE (secondary prevention of cardiovascular disease in the elderly), are expected in 2022.
The trial will compare the polypill against standard treatment (where patients take drugs separately) among individuals at high risk of CVD – those aged over 65 years who have had a myocardial infarction or who have an additional cardiovascular risk factor, such as diabetes or chronic kidney disease, and those aged over 75 years. Castellano is hopeful that the polypill’s effect on adherence among this high-risk population will show a difference in cardiovascular outcomes. “If they’re not well treated, [they] are very likely to show recurrence in events.”
Another source of outcomes data is the PolyIran study, the first large-scale, long-term, pragmatic randomised trial to investigate the effects of a polypill for CVD on primary or secondary prevention. Results from this five-year trial were published in August 2019
. It showed that a polypill containing aspirin, atorvastatin, hydrochlorothiazide and either enalapril or valsartan reduces the risk of major cardiovascular events, such as heart attack, stroke and heart failure, by 34% in patients aged over 50 years compared with lifestyle advice alone. The study was conducted in Iran and involved 6,838 participants.
Huffman says the PolyIran trial breaks new ground, demonstrating the effectiveness of polypills for the first time. “Further evidence reported from ongoing polypill trials may provide greater certainty about the estimated effect size,” he says.
Should the results of SECURE and TIPS-3 [a primary prevention trial] be positive, the polypill will be included in future clinical guidelines to improve cardiovascular prevention
Castellano goes further. “PolyIran is a huge step forward in supporting global implementation of the polypill as an effective alternative [to multipill regimens],” he says. “Should the results of SECURE and TIPS-3 [a primary prevention trial] be positive, the polypill will be included in future clinical guidelines to improve cardiovascular prevention.”
Although the polypill strategy is acknowledged within various clinical guidelines, most fall short of recommending FDCs. The 2018 European Society of Hypertension guidelines recommend the use of FDCs (or single-pill combinations), but the focus is on combinations of antihypertensive agents
. Grobbee sees this as a big step. “It opens the door for other polypill combinations in other guidelines,” he says.
Huffman agrees that inclusion in clinical guidelines will be an important step in implementing the polypill strategy and will standardise treatment pathways. “Scale-up of HIV therapy was driven by non-physician clinicians who adhered to clinical algorithms,” he points out.
Another route to widespread implementation of the polypill strategy is through inclusion in the WHO’s essential medicines list (EML), which would bolster take up in low- and middle-income countries.
Since 2013, three attempts to add polypills for CVD to the WHO’s EML have been unsuccessful.
In July 2018, at a meeting convened by polypill researchers at the London School of Hygiene and Tropical Medicine, Nicola Magrini, the secretary of the WHO’s EML committee, said that the applications for the polypill had failed because there was no strategy to support widespread adoption.
Such a strategy may come from the CDIC-Ferrer project in Latin America where, in Mexico, the public health system has agreed to pay for its polypill.
The way forward
Obtaining the full public health benefit of polypills will require education, advocacy and implementation by global agencies, as well as reimbursement by governments and other payers.
Webster and Huffman say that evidence is needed from demonstration projects on how to implement the polypill strategy on the ground.
“We still have to figure out what’s the best way to insert these into a health system,” says Webster.
Huffman adds: “It’s probably a combination of investment from pharmaceutical companies, health system investment to be able to accept and deliver these medicines, as well as additional empiric research demonstrating the potential benefits in broader populations, as well as the risks.”
Castellano emphasises that patients and payers need to be mobilised. “The cardiovascular pandemic right now resembles the HIV pandemic 20 years ago. We need to engage patients, payers and societies to acknowledge the fact that 80% of [cardiovascular] deaths worldwide are happening where people don’t have access to treatment,” he says. “Whether the polypill contains atorvastatin 40 or 80 should not be the central discussion. It’s a discussion about making sure people have access to, and can afford and follow, treatment.”
 World Health Organization, The Wellcome Trust. 2002. Available at: https://apps.who.int/iris/bitstream/handle/10665/42567/WHO_MPN_CVD_2002.01.pdf?sequence=1 (accessed September 2019)
 Castellano JM, Verdejo J, Ocampo Set al. Clinical effectiveness of the cardiovascular polypill in a real-life setting in patients with cardiovascular risk: The SORS Study. Arch Med Res 2019;50:31–40. doi: 10.1016/j.arcmed.2019.04.001