Once-daily polypill shows promise for CV prevention: PolyIran

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A once-daily, fixed-dose polypill including aspirin, atorvastatin, hydrochlorothiazide and enalapril or valsartan was effective for the prevention of major CV events in adults living in low- and middle-income regions, with high adherence and low adverse events.

According to a new study published in The Lancet, in a cohort of participants living in the low- to middle-income Golestan region of Iran (n = 6,838; aged 40-75 years; 50.4% women; 10.8% preexisting CVD; 15% diabetes), a once-daily polypill in combination with educational training on healthy lifestyle, diet, weight control, and abstinence from smoking and opium, resulted in a lower incidence of major CV events (HR = 0.66; 95% CI, 0.55-0.8) compared with participants who did not receive the polypill. Further, the reduction in risk for major CV events improved with greater adherence to the polypill (HR = 0.43; 95% CI, 0.33-0.55).

Additionally, the researchers reported no significant difference in CV outcomes if participants had preexisting CVD (HR = 0.61; 95% CI, 0.49-0.75) or no CVD (HR = 0.80; 95% CI, 0.51-1.12; P = .19).

“For clinical practice, the main message is that we should not wait until heart attack or stroke [occurs] and then start treatment. Rather, we should prevent heart attack and stroke in apparently healthy people who have one or more risk factors by starting prevention with a once-daily polypill, which is very safe,” Reza Malekzadeh, MD, director of the Digestive Disease Research Institute at the Tehran University of Medical Science, Iran, told Cardiology Today. “In low- and middle-income countries, we should [aim to prevent] heart attack and stroke, which is presently one of the major etiologies of premature death and disability. We can do this using polypill.”

Source: Adobe Stock

In other findings, the overall frequency of adverse CV events was similar between the minimal care group and the polypill group, for incidence of intracranial hemorrhage (polypill group, 0.6% vs. minimal care group, 0.3%) and gastrointestinal bleeding (polypill group, 0.4% vs. minimal care group, 0.3%).

The PolyIran study was a pragmatic, cluster-randomized trial nested in the Golestan Cohort Study. Researchers enrolled participants living in low- to middle-income areas in the Golestan region of Iran and divided participants into two groups: fixed-dose polypill treatment or minimal care. Both groups received educational training on a healthy lifestyle, diet, weight control, and abstinence from smoking and opium, which is a common practice among participants in this cohort. Educational training was provided by PolyIran field visit teams at 3 and 6 months, then every 6 months thereafter, with follow-up for 60 months.

The primary outcome was occurrence of major CV events, which included hospitalization for ACS, fatal MI, sudden death, HF, coronary artery revascularization procedures, and non-fatal and fatal stroke.

The polypill administered to participants contained aspirin 81 mg, atorvastatin 20 mg, hydrochlorothiazide 12.5 mg and enalapril 5 mg, unless a participant developed a cough, in which case he or she was switched to a formula containing valsartan 40 mg instead.

Median adherence to the polypill tablets was 80.5% (interquartile range, 48.5-92.92).

The researchers noted that research and extended follow-up will continue.

“This study was performed in rural North east Iran and 80% of participants were Turkmen,” Malekzadeh said. “We are presently doing another trial in Southern Iran where the ethnicity is 80% Persian, including participants who are somewhat more prone to heart attack and stroke, to ensure that the results of this study is generalizable to different ethnicities.” – byScott Buzby

Daily polypill plus aspirin lowers risk for CVD, death

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Adults at intermediate CV risk assigned a polypill plus aspirin were 31% less likely to experience a CV event or death compared with those assigned double placebo over a nearly 5-year period, according to new data from the TIPS-3 trial.

“The most important finding is that the combination of a polypill — which includes multiple BP-lowering drugs plus statins — plus aspirin reduced the risk for cardiovascular disease, stroke or death by 30% among those who were randomized, and up to 40% among those who actually took the medicines, Salim Yusuf, MD, DPhil, FRCP, FACC, the Marion W. Burke Chair in Cardiovascular Disease and director of the Population Health Research Institute at McMaster University Medical School, told Healio.

The observed CV benefits of a daily polypill-plus-aspirin regimen were lower than the original hypothesized benefits; however, the findings are still important for the primary prevention population, Yusef said during a press conference at the virtual American Heart Association Scientific Sessions. If half of eligible adults were prescribed a polypill with aspirin, as many as 5 million CV events could be avoided globally, he said.

“I should hasten to add, this is important for the ‘rich’ countries and the poor countries,” Yusuf said.

Study design

Salim Yusuf

Yusuf and colleagues analyzed data from 5,713 adults without CVD at baseline who had an elevated Interheart Risk Score. Researchers randomly assigned participants to receive a once-daily polypill containing 40 mg simvastatin, 100 mg atenolol, 25 mg hydrochlorothiazide and 10 mg ramipril or once-daily placebo; 75 mg aspirin or placebo; or vitamin D or placebo monthly. (Vitamin D was assessed, but those results were not presented here.)

For the polypill-alone and polypill plus aspirin comparisons, the primary outcome was CV death, MI, stroke, resuscitated cardiac arrest, HF or revascularization. For the aspirin comparison, the primary outcome was CV death, MI or stroke. The cohort was followed for 4.6 years.

The findings were simultaneously published in The New England Journal of Medicine.

For the last 18 months of the study, Yusuf noted there was a “substantial decline” in adherence to therapies, due to difficulties getting medications to participants and resupply issues related to the COVID-19 pandemic.

Benefits of polypill alone

Researchers observed a 21% relative risk reduction in CV events for participants assigned polypill therapy vs. placebo (HR = 0.79; 95% CI, 0.63-1), with curves diverging at 6 months after therapy initiation, Yusuf said. In prespecified sensitivity analyses accounting for nonadherence due to nonmedical reasons, participants assigned polypill therapy were 26% less likely to experience a CV event within 30 days of stopping the medication (HR = 0.74; 95% CI, 0.57-0.97).

“After stopping the medication, the number of events were identical, and within 30 days of stopping the medication, there is a 26% risk reduction,” Yusuf said.

Researchers found that polypill therapy had a modest effect on CV risk factors. The mean difference between the polypill and placebo groups in systolic BP reduction was 5.8 mm Hg (95% CI, 5.1-6.4); mean difference between groups for LDL cholesterol was 19 mg/dL (95% CI, 17.3-20.8).

“Initially, we saw a 10-mm Hg reduction in BP, but over time, this attenuated,” Yusuf said. “This cannot be explained by adherence decreasing over time. I think the body gets used to the effects of the BP lowering and there are compensatory mechanisms.”

LDL reduction, too, while significant, was “only about half of what we expected,” Yusuf said.

Benefits of polypill plus aspirin

Researchers observed a 14% relative risk reduction for the primary outcome among participants assigned aspirin alone (n = 2,860) vs. placebo (n = 2,853), for an HR of 0.86 (95% CI, 0.67-1.1). There was no excessive bleeding observed with aspirin vs. placebo, which Yusuf attributed to the lower, 75-mg dose.

“This is hopefully the best evidence yet that aspirin does have a benefit on top of other preventive strategies,” Yusuf said.

Participants assigned polypill plus aspirin (n = 1,429) were 31% less likely to experience a primary event during follow-up compared with those assigned double placebo (n = 1,421), with an HR of 0.69 (95% CI, 0.5-0.97), with event curves again diverging at 6 months, Yusuf said.

In sensitivity analyses adjusted for nonadherence due to nonmedical factors, researchers observed a 39% risk reduction for the primary outcome with polypill-plus-aspirin therapy vs. double placebo (HR = 0.61; 95% CI, 0.41-0.91).

“Each of the pill components contribute to the benefits of the combined therapy,” he said.

‘Consistency of effects’ across trials

During a discussion following the TIPS-3 presentation, Anushka Patel, MBBS, SM, PhD, FRACP, vice principal director and chief scientist at the George Institute for Global Health and professor of medicine at University of New South Wales Sydney, said TIPS-3 adds to the body of evidence demonstrating that polypill therapy significantly reduces CV risk in a primary prevention population.

“With TIPS-3, we now have direct evidence from three randomized trials that evaluated polypill-based strategies in more than 18,000 participants on, importantly, clinical outcomes,” Patel said during the press conference. “These three studies had some important differences, but the consistency of effects on prevention of major CV events is clear.”

Patel noted that risk factor reductions with the polypill were lower than anticipated; the reductions in BP and LDL cholesterol were about 40% of what might be expected with the individual component drugs, assuming 100% adherence to therapy. However, the polypill was shown to be safe and can provide important clinical and public health benefits, Patel said.

“If implementation and adherence challenges can be addressed at the system, prescriber and patient levels, the public health impact of polypill-based strategies could be enormous, particularly if the polypill is affordable,” Patel said. “This is where I believe future research should be prioritized.”

Reference:

Yusuf S, et al. N Engl J Med. 2020; doi:10.1056/NEJMoa2028220.

Perspective

Anubha Agarwal, MD, MSc

In TIPS-3, a polypill-plus-aspirin regimen led to a 31% lower relative risk for CV events during a mean of 4.6 years in a primary prevention population at intermediate CV risk. The direction and magnitude of this effect is congruent with what was observed in prior trials, including PolyIran, and provides additional evidence that a polypill-based approach is effective. The most urgent question now is what will be the regulatory proof needed to advance polypills to commercialization to make them available to our patients who are most likely to benefit?

Anubha Agarwal, MD, MSc

Cardiovascular Disease Fellow

Northwestern University Feinberg School of Medicine

Visiting Postdoctoral Research Fellow

The George Institute for Global Health

Polypill soon after heart attack lowers risk for major adverse CV events

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In older adults, a polypill containing aspirin, an ACE inhibitor and a statin within 6 months after myocardial infarction lowered the risk for major adverse CV events compared with usual care, according to results of the SECURE trial.

The polypill strategy consisted of aspirin 100 mg, ramipril 2.5, 5 or 10 mg and atorvastatin 20 or 40 mg.

Pills in shape of heart_Adobe Stock — *Source: Adobe Stock*

“Use of a cardiovascular polypill as a substitute approach could be an integral part of a broader strategy to improve secondary prevention,” Valentin Fuster, MD, PhD, director of Mount Sinai Heart, physician in chief of The Mount Sinai Hospital and general director of the National Center for Cardiovascular Innovation in Madrid, Spain, said in a press conference during the European Society of Cardiology Congress.

‘Striking’ reduction in risk

The phase 3, randomized, controlled SECURE trial enrolled 2,499 older adults who were randomly assigned to the polypill-based strategy or usual care, which consisted of taking the drugs separately at the treating physicians’ discretion according to current ESC guidance for this patient population. Patients were followed for 36 months.

The primary composite outcome of CV death, nonfatal MI, nonfatal ischemic stroke or urgent revascularization occurred in 9.5% of patients assigned the polypill-based strategy and in 12.7% assigned usual care (HR = 0.76; 95% CI, 0.6-0.96; P = .02).

Valentin Fuster

“The results were striking,” Fuster said during the press conference. “There are two points of importance. The curves begin to separate from the very beginning of the trial, and they continue to separate over time. So, one can begin to project the possibility that the results would be even more striking if the trial continues to move forward.”

The polypill-based strategy also lowered risk for the key secondary composite outcome of CV death, nonfatal type 1 MI or nonfatal ischemic stroke (8.2% vs. 11.7%; HR = 0.7; 95% CI, 0.54-0.9; P = .005).

The polypill was also safe. Adverse events were similar between the two groups, the researchers reported.

Death from any cause occurred in 9.3% of patients assigned the polypill-based strategy and 9.5% assigned usual care. Death from non-CV causes was slightly higher in the polypill group, at 5.4% compared with 3.7%, according to the results.

In addition, the treatment effect of the polypill for the primary outcome was similar across prespecified subgroups, including age, sex, location, prior vascular event, and presence or absence of diabetes or chronic kidney disease.

“It was completely consistent in the 16 (prespecified) groups in favor of the polypill vs. the pills taken conventionally,” Fuster said. “This really validates the importance of the study.”

The SECURE trial enrolled patients with recent type 1 MI within the previous 6 months. Median time from index MI to randomization was 8 days. Those enrolled were aged older than 75 years or at least 65 years or older with other risk factors such as diabetes, kidney dysfunction, and previous MI, coronary revascularization, CABG or stroke. The mean age was 76 years, 31% were women and the majority were white. Hypertension (78%), diabetes (57%) and history of smoking (51%) were common.

The trial was conducted at 113 centers in seven countries worldwide.

“The trial results are broadly applicable to the general population, especially considering that the average age at the time of a first myocardial infarction is now 65.6 years for men and 72 years for women, along with the high prevalence of diabetes mellitus, chronic kidney disease and previous coronary artery disease in these patients,” the researchers wrote in the simultaneous publication in The New England Journal of Medicine.

High adherence

The reductions in risk with the polypill observed in this trial “may be explained partly by increased adherence,” the researchers discussed in NEJM.

Overall patient-reported medication adherence was higher in the polypill group. At 6 months, high levels of adherence were observed in 70.6% of the polypill group and in 62.7% of the usual care group. This persisted at 24 months, when high levels of adherence were seen in 74.1% and 63.2%, respectively.

“Measuring adherence is always difficult, but we gave a survey of eight questions to determine high adherence, middle adherence and low adherence,” Fuster said at the press conference. “The results were very significant in favor of adherence to the polypill. Probably this is the most important reason of how this worked.”

Reference:

Castellano JM, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2208275.

Perspective

Steven E. Nissen, MD, MACC)

Steven E. Nissen, MD, MACC

This trial is a puzzle. The whole concept of the polypill is that you get much better adherence, better LDL and better BP reduction. In the SECURE trial, both the conventional treatment arm and the polypill arm had almost identical LDL, systolic BP and diastolic BP. So why was there a difference in outcomes? I don’t think it makes a good deal of sense. I am puzzled by it, as I am sure many people will be.

The reasons for the difference in outcomes were not really addressed in the manuscript. The authors talked about pleiotropic effects, which is what everybody says when they get a result they cannot explain. And I cannot explain the results. I cannot tell you that the results answer the question about the polypill in the absence of additional understanding of what is going on. The authors are going to have to do a lot of explaining.

I have been a skeptic about the polypill. I believe that good medicine is about individualizing care. Not everybody needs the same amount of BP reduction. I do not think it is a strategy for a sophisticated clinician in a higher-income country. It might be reasonable in low- or middle-income countries, but I still think it is a great puzzle. This trial takes us a little bit forward, but it leaves as many questions as it answers.

Steven E. Nissen, MD, MACC

Cardiology Today Editorial Board Member

Cleveland Clinic

Polypill Proves Its Mettle for Heart Protection Post-MI

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Trial affirms benefit of single drug-combo pill compared with usual care in secondary prevention

Combining aspirin, an ACE inhibitor, and a statin into a single “polypill” improved cardiovascular outcomes in secondary prevention compared with prescribing the medications separately, the SECURE randomized trial showed.

The polypill reduced the primary composite risk of cardiovascular death, nonfatal type 1 MI, nonfatal ischemic stroke, and urgent revascularization by a relative 24% over usual care, with a rate of 9.5% versus 12.7%, respectively (P=0.02), reported Valentin Fuster, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, during the European Society of Cardiology (ESC) Congress.

Looking at just the hard outcomes without revascularization likewise favored the polypill (8.2% vs 11.7%, HR 0.70, 95% CI 0.54-0.90).

“The use of a cardiovascular polypill as a substitute for several separate cardiovascular drugs could be an integral part of an effective secondary prevention strategy,” Fuster and colleagues wrote in their study, which was published simultaneously in the New England Journal of Medicine.

“By simplifying treatment complexity and improving availability, the use of a polypill is a widely applicable strategy to improve accessibility and adherence to treatment, thus decreasing the risk of recurrent disease and cardiovascular death,” they added.

The trial didn’t show much difference between groups in blood pressure or LDL cholesterol levels; rather, the researchers chalked the differences up to improved adherence leading to greater antiplatelet exposure, perhaps along with pleiotropic effects of statins and ACE inhibitors beyond those measures.

The trial was consistent with the propensity-matched NEPTUNO study, which showed a 27% reduction in major adverse cardiovascular event risk with a similar polypill in a secondary prevention setting, which was also attributed to higher medication persistence.

Moreover, the study’s results add to the evidence for the benefits of fixed-dose combo pills seen in primary prevention as well.

“There is a history here of 15 years,” noted Fuster at a press conference for the hotline trial session. The group first showed that adherence to medication after MI was a big problem, then showed in the FOCUS study that the polypill improved adherence. Fuster said that this advantage now translates into a “striking” clinical benefit.

Notably, the event curves began to separate for both the primary and key secondary endpoints right from the beginning and continued to do so at the median 3 years of follow-up in the trial, Fuster pointed out.

“I would like to emphasize one thing: that the impact of the data I presented is not different than the impact of aspirin,” he said. “We have in front of us something that could be simple and for countries middle-income and low-income, which is how we started the trial, it actually could be meaningful. But now the next step is we have to go to the agencies for approval.”

A combination pill with atorvastatin was approved for use in Europe but now it’s time to go to the FDA, he added.

Martha Gulati, MD, director of cardiovascular disease prevention at the Barbra Streisand Women’s Heart Center at Cedars-Sinai Heart Institute in Los Angeles, noted that the polypill wouldn’t just be useful in lower-income countries.

Access and cost are not just issues in the developing world, she argued, pointing to the less-than-perfect adherence achieved in the polypill group in the high-risk population studied.

High scores for adherence were seen at 6 months in 71% of the polypill group and 62.7% of usual care patients (risk ratio [RR] 1.13, 95% CI 1.06-1.20) and at 24 months in 74.1% and 63.2%, respectively (RR 1.17, 95% CI 1.10-1.25).

“That’s so telling, because you’ve had something that could kill you and is a pretty serious medical event and then people don’t take their medication,” Gulati noted. “A lot of patients who have had myocardial infarction, these are not the only drugs they’re on. They’re often on expensive antiplatelet agents, they may be on medications for diabetes, they might need more than just a statin eventually, they may need other lipid-lowering agents.”

“We put a great burden on our patients and a financial burden as well with every copay. So making it easy is something, to me, we should be interested in,” she said. “Even the generic drugmakers should have some interest in making it available.”

It’s really a public health problem, Fuster agreed. “People do not have adherence to what we know.”

The SECURE (Secondary Prevention of Cardiovascular Disease in the Elderly) trial included 2,499 patients ages 75 and older (or at least age 65 with an additional risk factor) who had type 1 MI in the prior 6 months.

They were randomized to treatment with a single daily pill containing aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (92% on 40 mg, and the rest on 20 mg based on patient history and blood test results) or usual care based on ESC guidelines.

Results were consistent across the countries where patients were enrolled (Spain, Italy, France, Germany, Poland, the Czech Republic, and Hungary), age (mean 76), sex (31% women), diabetes and kidney disease status, and prior revascularization.

“The trial results are broadly applicable to the general population,” Fuster’s group suggested, “especially considering that the average age at the time of a first myocardial infarction is now 65.6 years for men and 72.0 years for women, along with the high prevalence of diabetes mellitus, chronic kidney disease, and previous coronary artery disease in these patients.”

All patients were enrolled before the end of 2019 and followed for a median of 36 months, during which the COVID-19 pandemic likely kept some patients from trial visits.

Other limitations included a lack of adjustment for multiple comparisons of secondary outcomes, which made the lower cardiovascular death rate in the polypill group (3.9% vs 5.8%) only a hypothesis-generating finding.

Between COVID-19 and the 14% withdrawal rate, the trial enrolled fewer patients than planned and had a lower event rate than expected, dropping the statistical power for the primary endpoint below the anticipated 80% to a “rather limited” level, noted Louise Bowman, MBBS, of the University of Oxford in England, who served as the study discussant at the hotline trial session.

An extra 10 or so events would have tipped the results the other direction, she pointed out.

In addition, “there was no way to blind participants, but that instantly risks bias, especially when it comes to reporting outcomes and adherence, and probably affects willingness to attend study visits and have blood samples taken,” she added.

Bowman expressed surprise that the adherence didn’t decline much from 6 to 24 months. “There may be biases at play, perhaps the true difference is even greater … Samples might be obtained only from more adherent participants who are more able to attend clinics.”

Still, she agreed with Fuster that the early divergence in the event curves was very encouraging for a real impact.

“I would advise caution in overinterpretation, given the limitations,” she said. However, “I will leave you with a question to consider: Do we actually need a study of a polypill strategy in order to change practice? Or should we be asking if there are any good reasons why the polypill is not a good idea given everything we now know?”