乌鸦传媒

Fixed-dose combination therapies for cardiovascular prevention have been slow to gain traction, despite accumulating positive data over the years. Is it time for clinicians to push these polypills into mainstream clinical practice?

Combining preventive medications into one pill can be appealing for people already taking guideline-recommended lipid- and blood pressure-lowering drugs as separate pills. Polypills have the potential to simplify pharmacotherapy regimens, which has translated into and improved access to medications for in various studies.

Thus, proponents of the polypill concept have proposed its use in primary and secondary prevention of cardiovascular disease (CVD) -- perhaps even going as far as routine treatment for the elderly.

Indeed, studies in primary prevention support the safety and feasibility of fixed-dose combination therapies.

For instance, the Polycap polypill from India's Cadila Pharmaceuticals (containing simvastatin 40 mg, atenolol 100 mg, hydrochlorothiazide 25 mg, and ramipril 10 mg), with or without aspirin, was associated with reduced composite CVD events over 6 years in people at intermediate cardiovascular risk in the TIPS-3 trial.

More recently, a preprint report of the trial showed that the Trinomia polypill from Spain's Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III and Ferrer (containing aspirin 100 mg; simvastatin 40 mg; and ramipril 2.5, 5, or 10 mg) worked for the control of LDL cholesterol and systolic blood pressure at 16 weeks in high-risk individuals.

Yet an FDA-approved, broad-stroke CVD prevention indication for polypills is still missing. The Polycap and Trinomia products are not available in the U.S. market. Only Trinomia is marketed for CVD prevention in Europe.

At the same time, FDA has approved many fixed-dose combination pills for hypertension, and there are other polypills marketed for combination control of cardiovascular risk factors, such as the one that puts together the diabetes drug sitagliptin with simvastatin (Juvisync) and another containing bempedoic acid and ezetimibe (Nexlizet) for cholesterol reduction.

However, even available polypills are not widely used.

"I have tried to order some polypill combinations that exist [such as a calcium-channel blocker plus hydrochlorothiazide] but it is usually more expensive or not covered by insurers. This brings up the more important next step after FDA approval, [which] is ensuring coverage and creating inexpensive options for patients," said cardiologist Sadiya Khan, MD, MSc, of Northwestern University Feinberg School of Medicine in Chicago.

Other barriers to a population-based, polypill approach to CVD prevention include the difficulty of titrating polypill dosages when one drug component is not tolerated or not enough to treat the patient to their cholesterol or blood pressure goals.

Then there is the safety concern of unnecessarily overmedicating people. Gastrointestinal disorders, albeit not serious ones, were more frequent among polypill users in VULCANO.

"I think we are better off titrating individual medications, such as beta-blockers, nitrates, statins, and baby aspirin for coronary artery disease," said Rita Redberg, MD, MS, a cardiologist at UCSF Health.

"I hope that the FDA waits for randomized trial evidence of trials done in the U.S. of clinical benefit of [a polypill for CVD] prior to any approval. I would not prescribe it now, as there is no such data, and this pill carries all the risks of adverse effects from each of the multiple medicines in this pill," Redberg told 乌鸦传媒.

Yet money appears to be the key reason why pharmaceutical companies don't seem to be clamoring to develop CVD polypills. There is not much financial incentive: FDA approval of polypills containing generic components carries only a few years of , and the generic agent can be available for cheap as a separate pill.

Nevertheless, the demand for a polypill for CVD is there.

"I would be very interested in prescribing polypills with robust data to my patients," said Khan.

"This is a very exciting area to optimize CVD prevention. We know that the leading risk factors for CVD -- blood pressure, cholesterol, and diabetes -- are poorly controlled. There are also serious concerns about polypharmacy and the number of pills patients are being asked to take and keep track of. In addition, the idea behind polypills to combine more medicines at lower doses to lead to more effective and safe administration is very appealing," she said.

Clinicians are now awaiting results of the trial to see how its investigational polypill (containing aspirin 100 mg; atorvastatin 40 mg; and ramipril 2.5, 5, or 10 mg) fares in secondary prevention over at least 2 years in the elderly.

And what about going to the extreme of handing out polypills to the general population or everyone over a certain age?

Redberg cautioned against taking healthy people and labeling them as patients to be prescribed fixed-dose CVD therapies.

"Americans can easily access most needed medications and the polypill introduces risk, including taking healthy people and labeling them as patients. Even small improvements in lifestyle, like eating more fresh foods and fruits and vegetables, increasing physical activity such as walking, or doing any sport, and not smoking would have far more public health impact, and not carry the risks of a polypill," she said.

"Furthermore, it is not fun to take pills every day, and we should prescribe them where there is a clear benefit for patients," she added.

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