Highlights from the 65th American College of Cardiology Annual Scientific Session (ACC 2016)

This year's American College of Cardiology Scientific Session (ACC 2016) featured a good number of studies on drug therapies in both primary and secondary preventive settings. In this update, we will present some of the studies that may be of particular significance to the practising physician.

Optimal handling of the healthy

In the preventive section, the HOPE-3 (Heart Outcomes Prevention Evaluation 3) trial stole the limelight, first and foremost by strengthening faith in statins—this time by extending their potential benefit to racially and ethnically diverse subjects without cardiovascular disease who did not necessarily have elevated levels of LDL-cholesterol, C-reactive protein, hypertension, or diabetes.¹ In the cholesterol-lowering arm of the study, 5874 women aged ≥60 years and 6831 men aged ≥55 years with an intermediate risk profile were randomly assigned to receive either rosuvastatin 10 mg once daily or placebo. The mean baseline LDL-cholesterol level was ∼128 mg/dL, and was ∼30 mg/dL lower in the rosuvastatin arm than in the placebo arm at the end of the trial. After a median follow-up of 5.6 years, the first co-primary endpoint (the composite of myocardial infarction, stroke, and cardiovascular death) occurred significantly less frequently in the rosuvastatin group than in the placebo group [3.7% vs. 4.8%, hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.64–0.91; P = 0.002]. The findings were consistent among pre-specified subgroups. Statin therapy was well tolerated, with an absolute excess of only 1.1% (5.8% vs. 4.7%, P = 0.005) for muscle pain or weakness.

Conversely, HOPE-3 left us less optimistic regarding blood pressure lowering in such individuals.² The two-by-two factorial design allowed for randomization of the study population to low-dose antihypertensive therapy with candesartan 16 mg per day plus hydrochlorothiazide 12.5 mg per day vs. placebo. At 5.6 years, active treatment resulted in an average blood pressure lowering of 6.0/3.0 mmHg above that occurring with placebo. This did not manifest as a significantly lower risk of cardiovascular events when compared with placebo (4.1% vs. 4.4%, HR 0.93, 95% CI 0.79–1.10; P = 0.40), but more often led to symptomatic hypotension, dizziness, or light-headedness (3.4% vs. 2.0%, P < 0.001). Still, significantly lower rates of the first co-primary endpoint were found for participants belonging to the upper tertile of systolic blood pressure (>143.5 mmHg, who had a mean systolic blood pressure of 154.1 mmHg) who received active treatment vs. placebo (HR 0.73, 95% CI 0.56–0.94; P = 0.02 for trend). Finally, the investigators compared the 3180 subjects who were assigned to the combined intervention with the 3168 subjects who received dual placebo.³ The findings were overall in agreement with the two separate analyses, with no significant subgroup interactions. For now, it therefore seems reasonable not to initiate antihypertensive drug therapy in patients who do not have conventionally defined hypertension and are at low to intermediate risk for major cardiovascular events.

Lower is better

Further adding to the cholesterol saga and building on lessons already learned from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial),⁴ pooled data from all 10 phase 3 trials from the ODYSSEY programme, comprising 4974 patients treated with statin plus alirocumab, placebo, or ezetimibe, demonstrated a continuous relationship between reduced on-treatment LDL-cholesterol levels and major adverse cardiovascular events, defined as death from coronary artery disease, myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization [HR 0.76 (95% CI 0.63–0.91) per mmol/L reduction, P = 0.003).⁵ Despite the small number of events, these results are quite encouraging and raise the expectations for the ongoing ODYSSEY Outcomes trial, which will randomize ∼18 000 patients with a recent acute coronary syndrome to either alirocumab or placebo for up to 64 months.⁶

But mechanisms still matter

Nonetheless, the tale of lower LDL-cholesterol levels always being better may not be so straightforward after all. The ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial, in which 12 092 patients at high cardiovascular risk were randomized to evacetrapib 130 mg once daily vs. placebo for 30 months, was terminated prematurely due to futility.⁷ Although the study drug significantly raised HDL-cholesterol levels by 130% (P < 0.001) while reducing LDL-cholesterol levels by 37% (P < 0.001), the primary endpoint, a composite of myocardial infarction, coronary revascularization, unstable angina, stroke, or cardiovascular death was almost identical in the two groups (evacetrapib 12.8% vs. placebo 12.7%; P = 0.85). Adding this to the negative findings for other cholesteryl ester transfer protein inhibitors, this target might not be as promising as it once seemed. Therefore, it is not just the reduction in LDL-cholesterol that counts, but how that goal is actually achieved.^8,9

New pair of wings for extended antiplatelet regimens

Extended dual antiplatelet therapy (DAPT) was a major area of interest in 2015, and at ACC 2016 two important pre-specified subgroup analyses from the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin – Thrombolysis in Myocardial Infarction 54) trial were presented. In the overall study, patients on low-dose aspirin with a prior myocardial infarction within the last 1–3 years and additional high-risk features were randomized to either ticagrelor (60 or 90 mg twice daily) or placebo. Both ticagrelor regimens significantly reduced the incidence of myocardial infarction, stroke, or death from cardiovascular causes, but at the cost of an excess of major bleeding.¹⁰ The 60 mg twice-daily dosing regimen caused less bleeding and dyspnoea than 90 mg twice daily, with consequently better adherence.

Given that patients with concomitant diabetes and prior myocardial infarction are at particularly increased risk for cardiovascular events, the first substudy tested whether the safety and efficacy of extended DAPT differed between subjects with (n = 6806) and without diabetes (n = 14 255).¹¹ At a median follow-up of 33 months, the risk of ischaemic events was significantly higher among diabetic patients vs. non-diabetic patients (11.6% vs. 7.8%, adjusted HR 1.45, 95% CI 1.22–1.73; P < 0.001). Ticagrelor resulted in similar relative risk reductions in cardiovascular events in patients with and without diabetes (P = 0.99 for interaction). However, there was a greater absolute risk reduction in diabetic patients vs. non-diabetic patients (1.5% vs. 1.1%). Furthermore, ticagrelor significantly reduced the risk of cardiovascular death in diabetic patients (ticagrelor vs. placebo, HR 0.78, 95% CI 0.61–0.99; P = 0.0495), but not in non-diabetic patients. There was also a significant reduction in coronary heart disease deaths in the diabetic patients treated with ticagrelor. Irrespective of diabetes, an increase in major bleeding with extended DAPT was observed (absolute risk difference, 1.6% in diabetic patients vs. 1.3% in non-diabetic patients; P = 0.89 for interaction).

Similar to diabetes, the presence of peripheral artery disease (PAD) in patients with prior myocardial infarction elevates the risk of atherothrombotic cardiovascular events, and such patients may benefit to a greater extent from long-term DAPT.¹² A total of 1143 patients from PEGASUS-TIMI 54 had PAD at baseline. At 3 years, the rate of myocardial infarction, stroke, or death in the placebo group was significantly higher in subjects with PAD vs. those without (19.3% vs. 8.4%, adjusted HR 1.60, 95% CI 1.20–2.13; P = 0.001). The relative risk reduction with ticagrelor was similar between patients with and without PAD (P = 0.41 for interaction), but, given their greater baseline risk, the absolute risk reduction was larger among PAD patients (4.1% vs. 1.0%). Furthermore, ticagrelor reduced the risk of acute limb ischaemia or peripheral revascularization in the overall trial. The increase in major bleeding observed with extended DAPT was consistent among patients with and without PAD (absolute risk difference, 0.12% vs. 1.46%; P = 0.28 for interaction). Taken together, these studies provide new insights on high-risk patient populations that should receive particular attention when deciding whether to extend a DAPT regimen beyond the traditional 12-month period in patients with prior myocardial infarction.

Maximizing gastrointestinal safety

A post-hoc analysis of the randomized COGENT (Clopidogrel and the Optimization of Gastrointestinal Events) trial showed that the gastrointestinal (GI) protection provided by proton pump inhibition (PPI) with omeprazole 20 mg in patients receiving DAPT with aspirin and clopidogrel did not depend on aspirin dose.^13,14 Patients on low-dose aspirin (75–81 mg, n = 2480) were at significant risk for the primary composite endpoint of GI bleeding, ulcer, and other endoscopy-confirmed pathology, with rates comparable with patients on high-dose aspirin (150–325 mg, n = 1272): 180-day Kaplan–Meier estimates, 2.1% vs. 1.7%. Treatment with omeprazole was associated with a significant reduction in GI events in both the low- and high-dose aspirin groups (absolute risk reduction, 1.9% vs. 1.7%; P = 0.80 for interaction) and did not result in excess cardiovascular events in either group. Other than being on DAPT, COGENT patients would not be considered to be at high risk of GI bleeding, but these data certainly support appropriate use of PPI in patients on DAPT at high GI risk, irrespective of whether they are on low- or high-dose aspirin—though other data suggest low-dose aspirin instead of high-dose aspirin should probably be preferred for chronic cardiovascular therapy.

Thus, there were several studies presented at ACC 2016 that were particularly relevant to those interested in pharmacotherapy and that have the potential to impact clinical practice.

Conflict of interest: D.L.B. serves on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the Board of Directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; as Chair for the American Heart Association Quality Oversight Committee; as a member of Data Monitoring Committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees). Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Vice-Chair), VA CART Research and Publications Committee (Chair); has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; and royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); is a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical; is a trustee for the American College of Cardiology; and conducted unfunded research for FlowCo, PLx Pharma, and Takeda; and is a member of the executive committees of COGENT, ODYSSEY Outcomes, and PEGASUS-TIMI 54.

Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.