CV events

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:

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

HOPE-3: Statins with or without BP-lowering drugs reduce CV events in intermediate-risk patients

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Data from the HOPE-3 trial support the expanded use of statins in intermediate-risk individuals who do not have CVD, and indicate that statin therapy in combination with antihypertensive medications offers a 30% reduction in CV events, but only in participants with high BP.

The findings could eventually lead to development and use of a polypill for primary prevention, researchers reported.

“The implications for practice are huge — I think we certainly should consider using statins much more widely than we have used them thus far,” Salim Yusuf, MBBS, DPhil, professor of medicine at McMaster University and executive director of the Population Health Research Institute of McMaster University and Hamilton Health Sciences, said in a press release. “In particular for patients with hypertension, our study suggests you can essentially double the benefit of lowering [BP] in hypertensives if you also lower cholesterol simultaneously.”

Salim Yusuf, MBBS, DPhil

Salim Yusuf

Yusuf said during a press conference at the American College of Cardiology Scientific Session that “this was the first formal testing of the polypill concept on clinical events.

“The trial demonstrated that the concept is valid in people with elevated BP. In others, there is no benefit,” he said. The findings were also published in three articles in the New England Journal of Medicine.

The 2-by-2 factorial trial included 12,705 people in 21 countries. Eligibility for enrollment was based on age and presence of at least one CV risk factor, but not on baseline lipid level. The researchers investigated the effectiveness of rosuvastatin (Crestor, AstraZeneca) 10 mg/day and candesartan 16 mg/day plus hydrochlorothiazide 12.5 mg/day as well as the combination of the two therapies in reducing CV events in patients at intermediate risk for CVD. The first co-primary outcome was the composite of death from CV causes, nonfatal MI or nonfatal stroke and the second co-primary outcome was resuscitated cardiac arrest, HF and revascularization. Median follow-up was 5.6 years.

CV benefit of BP-lowering medications

In the primary analysis of the trial, the effectiveness of candesartan (16 mg/day) plus hydrochloride (12.5 mg/day) was compared against a placebo.

“One of the unique features of the main study results was that it allowed a relatively wide range of BP entry levels,”Eva Lonn, MD, FACC, a cardiologist and professor of cardiology at McMaster University and senior scientist at the Population Health Research Institute, said at the press conference. “This is why we were successful in conducting some subgroups in the trial.”

Eva Lonn

According to the results, there was a 6 mm Hg systolic/3 mm Hg diastolic greater decrease in BP in the treatment group than in placebo, and 260 participants (4.1%) in the treatment group experienced the first coprimary endpoint compared with 279 (4.4%) in the placebo group (HR = 0.93; 95% CI, 0.79 -1.1; P = .4).

Three hundred and twelve participants (4.9%) in the treatment group met the secondary primary endpoint versus 328 (5.2%) of those assigned placebo (HR = .95; 95% CI, 0.81 to 1.11; P = .51) in the placebo group. However, in a subgroup analysis of patients with systolic BP >143.5 mm Hg, significant reductions were observed in both primary endpoints.

“Overall in this population, the [BP]-lowering drugs had no clear benefit, but in those with higher [BP] before therapy — over 143.5 mm Hg — the treatment was effective. However, there was no benefit in those with lower [BP] and even a tendency towards harm in those in the lowest third of the [BP] distribution,” Lonn said.

Targeting both cholesterol and BP

In a secondary analysis, participants were randomized to either rosuvastatin 10 mg/day and candesartan 16 mg/day plus hydrochlorothiazide 12.5 mg/day (n = 3,180) or to dual placebo (n = 3,168). The researchers observed that participants assigned the combined treatment experienced a reduction in CV events.

“Most of the hypertension guidelines right now focus on what agents to use and what [BP] to aim for, and there has been very little emphasis on the importance of statins in treating patients with hypertension,” Yusuf said in a press release.

“Our approach, which used a combination of moderate doses of two [BP]-lowering-drugs plus a statin, appears to produce the biggest ‘bang,’ in terms of reducing events, with few side effects,” he said.

One hundred thirteen (3.6%) participants in the combined treatment group experienced the first coprimary endpoint compared with 157 (5%) from the dual placebo group (HR = 0.71; 95% CI, 0.56 to .90; P = .005). A reduction in the second coprimary endpoint was seen as well, 4.3% in combined therapy group vs. 5.9% in the dual placebo group (HR = 0.72; 95% CI, 0.57 to 0.89; P = .003).

In addition, those in the combined therapy group had a 33.7 mg/dL-greater decrease in LDL level and a 6.2 mm Hg-greater decrease in systolic BP than those in the dual placebo group.

Expanding statin use

In another analysis, the broad application of statins to an ethnically diverse population at intermediate risk was evaluated.

“Unique features of this arm of the trial included that there was no entry criteria based on lipid levels, no routine monitoring through the study, and no dose titration,” Jackie Bosch, PhD, associate professor of rehabilitation science at McMaster University and director of the prevention program at the Population Health Research Institute, said at the press conference.

Mean LDL cholesterol level was reduced 26.5% in the rosuvastatin group compared with the placebo group, according to the results. Two hundred and thirty-five participants (3.7%) in the rosuvastatin group vs. 304 participants (4.8%) in the placebo group (HR = 0.76; 95% CI, .64-.91; P = .002) met the first coprimary endpoint. Similar results were found with the second coprimary endpoint: 277 patients (4.4%) in the rosuvastatin group vs. 363 participants (5.7%) in the placebo group (HR = 0.75; 95% CI, 0.64 to 0.88; P < .001).

“There were consistent benefits regardless of baseline LDL cholesterol, systolic BP, CV risk and ethnicity,” Bosch said.

The researchers noted a longer follow-up might be needed to see the full effects of the therapies, and that they plan on continuing follow-up for another 3 to 5 years and to further analyze possible ethnic and geographic differences.

In an editorial published in NEJM, William C. Cushman, MD, of the Veterans Affairs Medical Center in Memphis, TN and David C. Goff, Jr., MD, PhD, of the Colorado School of Public Health at the University of Colorado, wrote that “these results support a risk-based approach to statin use, which has been recommended in recent guidelines, rather than an approach that is based primarily on LDL cholesterol levels, and the results add to the evidence supporting statin use for primary prevention.”

Cushman and Goff pointed out that while “neither of the drugs for BP lowering that were used in the trial have been shown to reduce the risk of CV events at such low doses … if higher doses had been used, the risk of CV events might have been significantly reduced, whether from greater BP lowering, additional effects of the antihypertensive drugs or both.”

 “These results may help to define the combined threshold of systolic [BP] (< 140 mm Hg) and [CV] risk (< 5%) below which the use of [BP]-lowering medications may not be useful in the short-term. However, these results do not rule out the possibility of a benefit with longer-term treatment in a portion of this relatively low-risk population,” Cushman and Goff wrote. – Tracey Romero

AACE releases position statement on testosterone therapy, CV events

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The American Association of Clinical Endocrinologists recently issued a position statement, published in Endocrine Practice, citing lack of evidence linking testosterone replacement therapy with cardiovascular events.

Neil Goodman, MD, FACE, of the University of Miami Miller School of Medicine, and colleagues for the AACE Reproductive Endocrinology Scientific Committee are calling for larger studies that will focus on the impact of testosterone replacement therapy on risk for CVD.

The association of low testosterone concentrations with CV problems, especially among older men, has been supported by recently published studies, but the position statement notes that low testosterone is often a marker of CV illness and not a causal factor.

Testosterone replacement therapy has been shown to have benefits in men with hypogonadism, including decreased insulin resistance, waist circumference and fat mass. Metabolic syndrome has also been reversed in some men following testosterone replacement therapy.

According to the committee, a thorough diagnostic work up should be performed on any man being considered for testosterone replacement therapy. The patients’ signs, symptoms and testosterone concentrations should guide the decision for the therapy rather than the underlying cause.

The committee added that the risk/benefit ratio of testosterone replacement therapy is still not completely clear.

“It needs to be emphasized that low testosterone is often a marker for chronic disease, and the underlying CVD risk factors should be addressed,” the researchers wrote. “In patients with vascular and minor symptoms of hypogonadism, a more cautious approach towards testosterone therapy is prudent. Physicians should have a detailed discussion with such patients … before embarking on testosterone replacement.” – by Amber Cox

PCSK9 inhibition better than standard therapy for cholesterol-lowering

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PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibition is showing significant promise in reducing cardiovascular (CV) events with effective cholesterol-lowering, based on impressive results from the OSLER-1 and -2 (Open-Label Study of Long-Term Evaluation Against LDL-C) trials.

OSLER-1 and -2 showed that the investigational PCSK9-inhibitor evolocumab (Repatha, Amgen) along with standard therapy, reduced LDL-cholesterol (LDL-C) by 61 percent vs standard therapy alone; from a median 120 mg/dL to 48 mg/dL after a median 11.1 month follow-up (p<0.001). [N Engl J Med 2015, e-pub 15 March, doi:10.1056/NEJMoa1500858]

In a prespecified exploratory analysis, evolocumab also reduced the incidence of CV events, defined as death, MI, unstable angina, coronary revascularization, stroke, transient ischemic attack, or heart failure, at 1 year (0.95 percent) vs standard therapy alone (2.18 percent) (p=0.003). This 53 percent reduction with evolocumab was consistent across each major CV event.

“The reduction in LDL-C was profound and that may be why we saw a marked reduction in CV events so quickly,” said Dr. Marc Sabatine of the Brigham and Women’s Hospital in Boston, MA, USA, a TIMI (Thrombolysis in Myocardial Infarction) Study Group investigator and lead author of OSLER-1 and -2.

“It suggests that if we can drive a patient’s LDL-C down a large amount to a very low level, we may start to see a benefit sooner than would be expected with a more modest intervention.”

These results follow similar results with the PCSK9-inhibitor alirocumab (Praluent, Sanofi/Regeneron), presented earlier at the 2015 European Society of Cardiology Congress, which showed a 61 percent reduction in LDL-C vs a 1 percent increase with placebo (p<0.0001). [N Engl J Med 2015, e-pub 15 March, doi:10.1056/NEJMoa501031]

“We now have many studies in a variety of different populations where we’ve seen the ability of these drugs to significantly reduce LDL-C,” said Sabatine. “And all the data we have point to the fact that the reduction in clinical events is tied to the reduction in LDL-C.”

In the open-label OSLER trials, 4,465 patients who had participated in 1 of 12 previous parent trials of evolocumab were randomized to receive intravenous evolocumab 140 mg every 2 weeks or 420 mg monthly plus standard therapy or standard therapy alone.

Adverse events occurred similarly between the two arms, however, evolocumab was associated with slightly more neurocognitive events.

An ongoing trial to study the effect of evolocumab on CV outcomes is expected to answer key questions regarding its clinical potential. The study, involving 27,500 patients, is not expected to see results until 2017.