ACC.17: A Look at the Science

Expand Your Thinking! This banner encouraging attendees hung over the stage in the Main Tent at ACC.17 – where the results from Late-Breaking Clinical Trials and Featured Clinical Research presentations presented there have provided plenty of findings for expanding our thinking and evaluating their impact on clinical practice. LDL-C reduction with PCSK9 inhibitors was big news this year, led by the FOURIER study, along with studies looking at cognitive function and drug access. Transcatheter aortic valve replacement (TAVR) was a big topic, with the SURTAVI trial being the biggest news, along with plenty of registry and observational data. Don’t miss a review of studies of antithrombotic therapy, oral anticoagulation and more in the feature article, More Challenges, More Insights: Another Dip into ACC.17.

FOURIER and EBBINGHAUS

The much-anticipated results of the FOURIER study at last have provided a look at hard outcomes with a PCSK9 inhibitor. Evolocumab added to statin therapy in patients with clinically evident atherosclerotic cardiovascular disease produced a significant 15 percent reduction in the primary endpoint – a composite of myocardial infarction (MI), stroke, hospitalization for angina, revascularization or cardiovascular death (11.3 percent with placebo, 9.8 percent with evolocumab). For the secondary endpoint of cardiovascular death, MI or stroke, there was a 25 percent reduction after the first year. Read More >>>

Cardiovascular mortality was not reduced, but statistically significant reductions were seen for MI (27 percent) and stroke (21 percent). The reductions in the primary and key secondary endpoints were consistent across all the key subgroups, including dosing regimen of evolocumab and baseline LDL-C levels, including those with the lowest quartile of LDL-C – starting at 74 mg/dL – in whom evolocumab reduced LDL-C down to 22 mg/dL.

FOURIER included 27,564 patients on a moderate- to high-intensity statin regimen followed at 1,272 sites in 49 countries. Most patients (81 percent) had a history of MI, 19 percent had suffered an ischemic stroke and 13 percent had symptomatic peripheral artery disease. The median baseline LDL-C was 92 mg/dL. To be included, patients had an LDL-C ≥70 mg/dL or a non–high density lipoprotein cholesterol ≥100 mg/dL and were on optimized statin therapy. Exclusions included an acute MI or stroke within the previous four weeks, advanced heart failure, uncontrolled heart rhythm disorders, planned cardiac surgery and end-stage kidney disease.

Patients were randomly assigned (1:1) to receive subcutaneous injections of evolocumab (either 140 mg every two weeks or 420 mg every month based on patient preference) or matching placebo. LDL-C was reduced by 59 percent with evolocumab, from a median of 92 to 30 mg/dL, which remained steady throughout the duration of the study.

The rate of adverse events, including allergic reactions, neurocognition, new-onset diabetes and muscle-related problems, were the same in both study arms. Rates of injection site reactions were slightly more common with evolocumab (2.1 vs. 1.6 percent), but most were mild and the overall rates of stopping the study drug due to suspected treatment-related adverse events were low and similar in both groups (1.6 and 1.5 percent). Only 0.3 percent of patients developed antibodies that could bind evolocumab and none interfered with the drug.

Yet, the relatively short follow-up (mean 2.2 years) is a limitation of the study, and PCSK9 inhibitors remain to be studied in other high-risk populations, acknowledged Marc S. Sabatine, MD, FACC, who presented the study.

"Given this was a relatively short trial, I fully expect larger benefits to accrue over the long-term. FOURIER provides high-quality evidence that evolocumab works, and I felt fortunate after ACC.17 to bring this information back to my patients in lipid clinic as we work together to optimize their preventive therapy." Seth Martin, MD, FACC

“FOURIER was an exciting way to kick off ACC.17,” says Seth Martin, MD, FACC. “Given this was a relatively short trial, I fully expect larger benefits to accrue over the long-term. FOURIER provides high-quality evidence that evolocumab works, and I felt fortunate after ACC.17 to bring this information back to my patients in lipid clinic as we work together to optimize their preventive therapy,” he adds.

Results from EBBINGHAUS, the prospectively planned cognitive sub-study of FOURIER – aptly named for the German psychologist and father of the study of human memory, Hermann Ebbinghaus – “alleviate concerns that very low cholesterol levels, such as those achieved with the combination of a PCSK9 inhibitor and statin, would negatively impact cognitive function,” says Sandra Lewis, MD, FACC.

The neurocognitive function of 1,974 patients (average age 63 years, 28 percent women) was evaluated using the Cambridge Neuropsychological Test Automated Battery, completed by patients at study entry and at 24, 48 and 96 weeks and at the end of the study to assess executive function, working memory, memory function and reaction time. They also completed a questionnaire assessing their everyday cognition before, during and at the end of the study.

“Patients who reached very low LDL values – less than 25 mg/dL – had cognitive function that was similar with those with higher LDL values,” says Robert P. Giugliano, MD, SM, FACC, who presented the study.

The mean change in the primary endpoint of executive function as measured by the Spatial Working Memory strategy index was minus 0.29 with placebo and minus 0.21 with evolocumab (p for non-inferiority < 0.0001). The outcomes for all secondary endpoints were similar for placebo and evolocumab. Also similar were the patient self-reports via the questionnaire and the investigator-reported cognitive adverse events for both placebo and evolocumab.

“Physicians and patients can be comfortable that the improvement in cardiovascular risk seen in the overall FOURIER study did not come with decline in cognitive function throughout the study period. Long-term term follow-up data are needed to add further support,” says Lewis.

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Insights on PCSK9 Approvals

“The results of the long-awaited FOURIER study may not have provided the ‘slam-dunk’ cardiologists were hoping for to gain easier access to PCSK9 inhibitor therapy,” says Eugene Yang, MD, FACC. “An anemic relative risk reduction for the primary endpoint and lack of a cardiovascular mortality benefit will likely raise more questions about the appropriate subset of patients for whom to offer this therapy,” he adds. Read More >>>

A snapshot of access to PCSK9 inhibitors during the first year after their approval by the U.S. Food and Drug Administration has shown that access is limited, with less than a third ever receiving the drug after its prescription, and that rejection rates vary by payer and pharmacy benefit manager.

Ann Marie Navar, MD, PhD, and colleagues examined the fate of the first prescription for PCSK9s in 45,029 patients (median age 66 years, 51 percent women) between August 1, 2015 and July 31, 2016, using a database encompassing 90 percent of retail, 60 percent of mail order and 70 percent of specialty pharmacies. The prescriber was a cardiology practice for 48.2 percent and for 36.9 percent it was a general practice.

The prescription was initially rejected for 79.2 percent of patients. Ultimately, the PCSK9 prescription was approved for nearly half (47.2 percent) of patients – but about a third (34.7 percent) never filled the prescription. The median time to approval was three days. The median time to dispensing was 9.9 days and for 25 percent of patients it was more than a month.

" A deeper dive into the results of FOURIER is fundamental to identifying the patients most likely to benefit, but more importantly to find a sweet spot for insurers to cover this therapy based on cost-benefit analyses." Eugene Yang, MD, FACC

Variability in the rates of rejection within payers suggested that factors other than clinical contribute to the decision, said Navar. The rates of rejection ranged from 33.1 to 74.7 percent across pharmacy benefit managers, from 37.9 to 83.5 percent across government-paid insurance programs, and from 33.2 to 77.6 percent across commercial payers.

A prescription by a cardiologist was 60 percent more likely to result in receiving PCSK9 therapy, as was having commercial plus government health insurance and using a mail-order pharmacy. Patients in a coupon program were nearly 17-fold more likely to receive therapy.

Navar noted that the prior authorization processes need to balance cost containment efforts and provider burden, and that the prolonged time to dispensing of the drug could have an impact on utilization and provider willingness to prescribe the drug.

While this study provides some insights into the challenges of obtaining approval for PCSK9 therapy, no data were presented to understand whether the prescribing was for appropriate patients and whether they were being optimally treated with statins with or without ezetimibe. “A deeper dive into the results of FOURIER is fundamental to identifying the patients most likely to benefit, but more importantly to find a sweet spot for insurers to cover this therapy based on cost-benefit analyses,” Yang says. <<< Return to top

The SPIRE Program

The SPIRE development program of the humanized PCSK9 inhibitor bococizumab has shown that the development of antidrug antibodies in 15-20 percent of patients attenuated the substantial reduction in LDL-C and that cardiovascular outcomes were similar with the drug and placebo. The results of the six parallel, multinational trials were presented by Paul M. Ridker, MD, MPH, FACC. Read More >>>

The cardiovascular outcomes studies, SPIRE-1 and SPIRE-2 were stopped prematurely in November 2016 after the lipid-lowering trial results led the sponsor to discontinue the drug’s development.

Results were reported for 4,449 high-risk patients (mean age 61 years, 42 percent women, LDL-C 122 mg/dL) who were treated with maximally tolerated doses of a statin (86 percent on high-intensity statin) and bococizumab 150 mg subcutaneously every two weeks or placebo.

In all six trials, the 55.2 percent reduction in LDL-C seen at 12 weeks with bococizumab was attenuated to 43 percent at 52 weeks – and this attenuation was greater (at 31 percent) in the 16 percent of patients who developed antibodies. The attenuation in LDL-C reduction was greater with higher antibody levels. Further, the reductions in LDL-C were highly variable within patients, regardless of antibody status.

Overall, the outcomes studies demonstrated a similar rate of major adverse cardiovascular events with bococizumab and placebo at 2.5 percent and 2.7 percent, respectively. However, this reduction was significant for patients with LDL-C ≥100 mg/dL in the SPIRE-2 trial but not in those with LDL-C ≥70 mg/dL in the SPIRE-1 trial. The event rate was 1.5 percent and 1.3 percent, respectively, for the combined endpoint of non-fatal MI, non-fatal stroke, hospitalization for unstable angina requiring urgent revascularization or cardiovascular death.

The investigators stated that the clinical benefits were greater and statistically significant in subgroup analyses in patients who had and sustained greater absolute and proportionate reductions in LDL-C and that this is consistent with the “lower is better for longer” hypothesis. They also state their data support the use of PCSK9 inhibitors on top of aggressive statin therapy in selected patients.

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ORION-1

A novel approach to lowering LDL-C, with the RNA interference drug inclisiran, provides significant, dose-dependent and sustained reductions at 180 and 240 days in patients at high cardiovascular risk, according to the results of the ORION-1 study presented by Kausik K. Ray, MD, MPhil, FACC. Read More >>>

Six different doses of inclisiran, which interferes with PCSK9 production, were examined in 501 patients (average age 63 years, 35 percent women) in the Phase II double-blind, placebo-controlled trial. About 69 percent of patients had atherosclerotic cardiovascular disease, 24 percent had diabetes, 5 percent had familial hypercholesterolemia and 13 percent were being treated for primary prevention. When they began the study, 73 percent of patients were taking a statin and 31 percent were on ezetimibe.

The primary endpoint of LDL-C reduction at 180 days was reduced by 27.9-41.9 percent with one subcutaneous injection and by 35.5-52.6 percent with two injections (p < 0.001). At 240 days, the reductions in PCSK9 and LDL-C remained significantly lower than at baseline with all the studied doses of inclisiran. Two injections of the 300 mg dose of inclisiran produced the greatest reduction in LDL-C, with 48 percent of patients receiving this dose achieving an LDL-C level <50 mg/dL. The average baseline LDL-C level was 128.2 mg/dL and baseline PCSK9 level was 424.3 ng/mL.

"The safety profile was excellent, and with the potential to ensure patient adherence via every six month injections, this drug has unique attributes that address several unmet clinical needs. We eagerly await a study of cardiovascular outcomes from the ORION-4 study." Richard Kovacs, MD, FACC

The rate of serious adverse events was 11 percent with inclisiran and 8 percent with placebo. Injection site reaction occurred in 5 percent of the patients receiving inclisiran. Injections are given every three or six months. The results of this study will inform the dose and dosing regimen for the Phase III cardiovascular outcomes study with this drug.

“The safety profile was excellent, and with the potential to ensure patient adherence via every six month injections, this drug has unique attributes that address several unmet clinical needs. We eagerly await a study of cardiovascular outcomes from the ORION-4 study,” says Richard Kovacs, MD, FACC.

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Tsimane Indians: Low Burden of CAD

The take-home message from a study of Tsimane Indians, a forager-horticulturalist population indigenous to the Bolivian Amazon, is quite strong, says Robert A. Vogel, MD, FACC: “Even in the presence of inflammatory stimuli, the majority of coronary artery disease (CAD) is due to our post-industrialized lifestyle with its consequential high burden of traditional risk factors.” He adds “this study should provide a strong stimulus for helping our patients through teaching better lifestyle patterns.” Read More >>>

The lowest reported levels of vascular ageing for any population studied were found in the Tsimane, with rates of coronary atherosclerosis five-times lower than in the U.S., according to results presented by Randall Thompson, MD, FACC. “The arteries of the Tsimane are 25-30 years younger than the arteries of sedentary urbanites. The data also show that the Tsimane arteries are aging at a much slower rate,” he said.

In the cross-sectional cohort study, researchers visited 85 Tsimane villages between 2014 and 2015 and took non-contrast CT scans of the hearts of 705 adults between the ages of 40 and 94. Based on the CT scans, 85 percent of the Tsimane people had no coronary artery calcium (CAC), 13 percent were at low risk with CAC scores between 1-100 and only 3 percent had moderate or high risk (CAC scores >100). Their mean LDL level was 91 mg/dL and HDL was 39.5 mg/dL.

"Even in the presence of inflammatory stimuli, the majority of coronary artery disease (CAD) is due to our post-industrialized lifestyle with its consequential high burden of traditional risk factors." Robert A. Vogel, MD, FACC

These findings continued into old age, where nearly two-thirds of those over 75 years old had almost no risk of heart disease and only 8 percent had moderate or high risk. By comparison, in a population of 6,814 people ages 45 to 84 in the Multi-Ethnic Study of Atherosclerosis, only 14 percent of Americans had no CAC and 50 percent had a moderate or high risk of CAD.

The lifestyle of the Tsimane Indians is characterized by a diet very low in fat and simple sugar, high in omega-3 and fiber, but not low in salt – and very high levels of physical activity (an average 16,000 steps a day; they were sedentary only about 10 percent of daylight hours). They had few traditional risk factors, but 48 percent had a C-reactive protein level >3 mg/L. <<< Return to top

SURTAVI

In the TAVR world, the SURTAVI trial was much-anticipated and it delivered, showing in patients considered to be at intermediate surgical risk that TAVR was non-inferior to surgical aortic valve replacement (SAVR) in patients with symptomatic, severe aortic stenosis. Read More >>>

The primary composite endpoint of all-cause mortality and disabling stroke at 24 months was similar at an estimated 12.6 percent and 14.0 percent in the TAVR and SAVR arms, respectively. “TAVR was just as good as surgery, but it was not statistically superior to it,” said Michael J. Reardon, MD, FACC, who presented the trial. The investigators used a modified intention-to-treat analysis that included patients in whom the procedure for their assigned group was attempted and used a novel Bayesian statistical model.

SURTAVI, conducted at 87 centers in the U.S., Canada, and Europe, is the first study to evaluate outcomes with the self-expanding CoreValve and the new Evolut-R bioprosthesis valves, used in 84 percent and 16 percent of TAVR patients, respectively. To allow for TAVR to be evaluated against real-world surgery, the surgeons performing SAVR could select any biologic valve or whether to enlarge the annulus or base of the valve.

"We saw the best surgical outcomes we’ve seen yet and TAVR did just as well. This is now the second randomized trial that has met its non-inferiority endpoint and should lead to changes in clinical guidelines that will move the field forward and also benefit our patients." Michael J. Reardon, MD, FACC

Patients had a mortality risk ≥3 and <15 percent based on The Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) score and overall clinical status including frailty, disability and comorbidity factors. The mean STS PROM score was 4.4 percent. About 60 percent had NYHA Class III/IV heart failure, but those with a SYNTAX score >22 were excluded. Mean patient age was 80 years and 44 percent were women.

Overall, deaths from any cause were similar for TAVR and SAVR: occurring in 2.2 versus 1.7 percent of patients at 30 days, 6.7 versus 6.8 percent at one year and in 11.4 versus 11.6 percent at two years. The rate of major disabling stroke at two years, 2.6 percent for TAVR and 4.5 percent for SAVR, was not statistically significantly different. Although not a primary outcome of the study, researchers noted that the risk of any type of stroke at 30 days was statistically superior for TAVR (3.4 percent vs. 5.6 percent for SAVR).

“We saw the best surgical outcomes we’ve seen yet and TAVR did just as well. This is now the second randomized trial that has met its non-inferiority endpoint and should lead to changes in clinical guidelines that will move the field forward and also benefit our patients,” Reardon said.

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Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Computed Tomography, Nuclear Imaging, Exercise

Keywords: ACC Publications, Cardiology Magazine, Angina, Unstable, Antibodies, Monoclonal, Aortic Valve, Aortic Valve Stenosis, Bayes Theorem, Biological Products, Bioprosthesis, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, Cognition, Coronary Artery Disease, Cost-Benefit Analysis, Cost Control, Cross-Sectional Studies, Diabetes Mellitus, Lipoatrophic, Diabetes Mellitus, Double-Blind Method, Exercise, Fibrinolytic Agents, Follow-Up Studies, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Hypersensitivity, Injections, Subcutaneous, Insurance Carriers, Intention to Treat Analysis, Kidney Failure, Chronic, Lipoproteins, Myocardial Infarction, Neuropsychological Tests, Patient Compliance, Peripheral Arterial Disease, Primary Prevention, RNA Interference, Registries, Risk Factors, Stroke, Surgeons, Tomography, X-Ray Computed, Transcatheter Aortic Valve Replacement, United States Food and Drug Administration, ACC Annual Scientific Session, ACC17


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