Quick catch-up on 6 key trials from AHA Scientific Sessions 2019

M3 India Newsdesk Nov 28, 2019

The recent American Heart Association (AHA) 2019 Scientific Sessions held between November 16 to 18 in Philadelphia, USA had a number of key, breaking trials presented, focusing on new approaches to risk reduction, drug interventions, and contemporary and interventional management, all of which potentially impact patient care.


Here are the highlights of the ORION-9, ORION-10, GALILEO, GALILEO 4D, TWILIGHT-ACS and the COLCOT trial that were presented this year.


ORION-9

Inclisiran reduced LDL by up to 50% in patients with familial hypercholesterolaemia. Inclisiran appeared to be able to address the unmet need of high-risk FH patients who were already on statins and ezetimibe.

In the trial, 482 patients with heterozygous familial hypercholesterolaemia (FH) were analysed over an 18-month period. All study participants had LDL levels greater than 100 mg/dL, were on a low-fat diet, and taking maximally tolerated statin doses.

The treatment group was given 300 mg of Inclisiran subcutaneously every 6 months (n = 242; median age, 56 years; 46% men; baseline LDL, 155 mg/dL) and compared with the placebo group (n = 240; median age, 56 years; 48% men; baseline LDL, 151 mg/dL).

Key finding: Inclisiran showed highly significant reductions in LDL versus placebo at 510 days (difference = –50%; P < .0001) and in a time-averaged analysis between 90 days and 540 days (difference = –45%; P < .0001).

All genotypes showed robust responses. Both groups had a similar safety profile. No liver, kidney, muscle or platelet toxicity was seen. There was no difference in serious adverse events in the groups. Minor or moderate injection-site reactions occurred in 9% of patients assigned Inclisiran vs. 0% with placebo.


ORION10

Inclisiran proved to be the first of a new class of cholesterol-lowering agents which was safe and easy to use since it comes in prefilled syringes. Its effects for lowering LDL are potent and durable and since it needs to be given only twice a year, this may have some impact on the clinical journey. Inclisiran would also not need to be co-administered with a PCSK9 inhibitor monoclonal antibody because both drugs would be targeting a similar pathway.

1561 patients with atherosclerotic cardiovascular disease already on statins were enrolled in the ORION-10 study. 95% of enrolled patients were on effective lipid-lowering therapy: 90% were taking statins, 79% were taking high intensity statins, and 10% were taking ezetimibe. The mean baseline LDL level was 105 mg/dL.

Patients were randomly given a subcutaneous injection of Inclisiran 300 mg or placebo at day 1 and day 30, then every 6 months thereafter for 18 months.

Key findings:

  • At the end of the study (day 510), LDL was reduced in the Inclisiran group by 58% vs placebo
  • From day 90 to day 540 the time-averaged reduction in LDL was 56% (P for both endpoints < .00001)
  • 7.4% patients in the Inclisiran group vs 10.2% patients in the placebo group experienced a prospective exploratory cardiovascular endpoint (MedDRA-defined cardiovascular non-adjudicated terms, including cardiac death, and any signs or symptoms of cardiac arrest, nonfatal myocardial infarction (MI), and/or stroke)
  • 0.9% patients in the Inclisiran group vs 0.6% patients in the placebo group had cardiovascular death, whereas a fatal/nonfatal MI or stroke was seen in 4.1% patients in the Inclisiran group vs 3.3% patients in the placebo group

Treatment emergent adverse events were similar in both groups. 2.6% of Inclisiran recipients versus 0.9% of placebo recipients were found to have injection site reactions which are similar to or less than that seen with PCSK9 monoclonal antibodies. The majority injection site reactions were mild. A few injection site reactions were moderate but none were severe or persistent.

Liver, kidney, and muscle enzymes were unaffected between the two groups. Serious adverse events, overall mortality, cardiovascular mortality, or cancer mortality between both groups was similar. 3.3% patients had new or worsening malignancy in both groups. Drug discontinuation secondary to adverse events was seen in 2.4% of Inclisiran recipients versus 2.2% of placebo recipients.


GALILEO, GALILEO 4D

GALILEO

Elderly patients who received anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban after TAVR had worse survival and experienced more thromboembolic and bleeding events than patients who received standard dual antiplatelet therapy (DAPT).

GALILEO enrolled 1644 patients who successfully underwent transcatheter aortic valve replacement (TAVR) and had no indication for an anticoagulant (i.e. no atrial fibrillation) from 136 sites in 16 countries between December 2015 and May 2018. Mean age of patients was 80.6 years (±6.6 years), of which, 49.5% were women. Two days (range, 0 – 8 days) was the median time from TAVR to randomisation.

An investigational anticoagulation strategy with the direct factor Xa inhibitor, rivaroxaban 10 mg once daily plus aspirin 75 to 100 mg once daily for the first 90 days followed by rivaroxaban alone was given to half of the patients randomly assigned to receive an antithrombotic strategy. The other half received aspirin 75 to 100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone as their antiplatelet-based strategy.

Key findings:

  • The primary efficacy outcome i.e. death or first thromboembolic event in the intention-to-treat analysis, was seen in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.01 – 1.81; P = .04)
  • The primary safety outcome i.e. major disabling or life-threatening bleeding was seen in 46 and 31 patients, respectively (HR, 1.50; P = .08)
  • The rivaroxaban group had a total of 64 deaths, and whereas in the antiplatelet group 38 deaths occurred (HR, 1.69; 95% CI, 1.13 – 2.53)

GALILEO 4D

The worse clinical outcomes in the main GALILEO trial far outweighed the positive outcomes with the rivaroxaban-based strategy's association with fewer valve abnormalities. Therefore, despite the positive imaging results seen in GALILEO 4D, 10 mg rivaroxaban-based treatment should not be routinely given after TAVR in patients who don't need anticoagulation.

The GALILEO 4D substudy used four-dimensional CT (4DCT) to evaluate functioning of the bioprosthetic aortic valves. 205 patients who underwent 4DCT 90 days after TAVR were evaluated in the substudy. Reduction of grade 3 or higher motion in at least one prosthetic valve leaflet was decided as the primary substudy endpoint.

Key findings:

  • In the rivaroxaban group, 2 of 97 patients (2.1%) had such a reduction as compared to 11 of 101 in the antiplatelet group (10.9%; P = .01)
  • Patients on rivaroxaban were less likely to show subclinical leaflet motion abnormalities and leaflet thickening. This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm
  • The proportion of patients with at least one thickened leaflet, which was the chief secondary endpoint, was seen in 12.4% of the patients in the rivaroxaban group and 32.4% of the patients in the antiplatelet group; this represented a 60% significant reduction by rivaroxaban

TWILIGHT-ACS

The main results of TWILIGHT demonstrated that switching 3 months after PCI to ticagrelor monotherapy from DAPT resulted in lowering of the bleeding risk without raising ischaemic risk. There was no excess ischaemic risk with ticagrelor monotherapy, irrespective of clinical presentation across different levels of risk, and regardless if the patient presented with unstable angina or non-STEMI. The relative bleeding risk reduction even increased to 51% in patients with ACS.

5,763 patients with non-ST-segment elevation ACS from TWILIGHT were chosen in TWILIGHT-ACS and results consistent with the main study were found in this substudy also. Ticagrelor monotherapy was found to reduce bleeding risk versus dual antiplatelet therapy with no additional ischaemic risk.

Key findings:

  • The rate of BARC 2, 3 or 5 major bleeding was 7.6% in the DAPT group with ticagrelor and aspirin compared with 3.6% in those assigned ticagrelor monotherapy (HR = 0.47; 95% CI, 0.36-0.61) at 1 year after randomisation, which occurred 3 months after PCI
  • Regardless of many risk factors the patients had (P for interaction = .69), results were consistent
  • Other prespecified bleeding endpoints that favoured ticagrelor monotherapy group at 1 year after randomisation included:
    • Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding: 0.8% vs. 2.1%; P < .0001;
    • TIMI major bleeding: 0.5% vs. 1%; P = .08;
    • GUSTO moderate or severe bleeding: 0.6% vs. 1.6%; P = .002; and
    • ISTH major bleeding: 0.9% vs. 2.2%; P = .001
  • Death, MI or stroke at 1 year, the primary ischaemic outcome was almost identical in both groups (monotherapy, 4.3%; DAPT, 4.4%; HR = 0.97; 95% CI, 0.74-1.28), regardless of the number of risk factors (P for interaction = .18).
  • Similarity was seen in prespecified ischaemic endpoints including:
    • CV death, MI or ischaemic stroke: monotherapy, 4%; DAPT, 4.2%; P = .77;
    • All-cause death: monotherapy, 1%; DAPT, 1.5%; P = .14;
    • Any MI: 3.1% in both groups; P = .99;
    • Ischaemic stroke: monotherapy, 0.5%; DAPT, 0.3%; P = .21; and
    • Definite or probable stent thrombosis: monotherapy, 0.4%; DAPT, 0.5%; P = .38
  • The effect of ticagrelor monotherapy was uniform across all levels of risk, and consistent results were seen regardless of patients having unstable angina or non-STEMI

A pooled analysis of TWILIGHT, GLOBAL LEADERS, SMART-CHOICE and STOPDAPT-2, also showed that the primary bleeding endpoint in those who had short-term DAPT followed by P2Y12 inhibitor monotherapy is reduced by 40% compared with those who had longer-term DAPT (HR = 0.6; 95% CI, 0.42-0.84), with no higher risk for MACE (HR = 0.91; 95% CI, 0.79-1.04). Even ACS patients show similar results with the relative bleeding risk reduction increasing to 51% (HR for bleeding = 0.49; 95% CI, 0.4-0.61; HR for MACE = 0.89; 95% CI, 0.73-1.09).


COLCOT

Adults with a recent MI, when given the anti-inflammatory gout medication colchicine, were less likely to have an ischaemic CV event over 2 years when compared with taking placebo, since colchicine 0.5 mg daily significantly reduced the risk for first ischaemic CV events by 23% and total ischaemic cardiovascular events by 34%.

This finding represented a landmark study since it repurposes a broadly available, relatively safe, generic drug such as colchicine to help solve the major public health issue of subsequent CV events post-MI in a cost-effective manner and helps patients overcome the cost barriers of expensive therapy globally.

4,745 adults were recruited within 30 days after MI in the COLCOT trial after which they were randomly assigned colchicine 0.5 mg once daily (n = 2,366) or placebo (n = 2,379). Mean patient age was 61 years- 19% patients were women and 20% patients had diabetes. 98.8%, 97.9% and 99% of participants, were taking aspirin, a different antiplatelet agent, and a statin respectively.

Mean index MI-to-randomisation time was 13.4 days, and 93% of participants underwent PCI for the index MI. A median follow-up of 22.6 months was done. CV death, resuscitated cardiac arrest, MI, stroke or hospitalisation for angina leading to coronary revascularisation was chosen as the primary endpoint and this occurred in 5.5% of participants in the colchicine group and in 7.1% of participants in the placebo group, for an HR of 0.77 (95% CI, 0.61-0.96).

Key findings:

  • For patients in the colchicine group, across five individual endpoints i.e. HR = 0.84 for CV death (95% CI, 0.46-1.52), 0.83 for resuscitated cardiac arrest (95% CI, 0.25-2.73), 0.91 for MI (95% CI, 0.68-1.21), 0.26 for stroke (95% CI, 0.1-0.7) and 0.5 for urgent hospitalisation for angina (95% CI, 0.31-0.81) a risk reduction was seen
  • The benefits of colchicine were magnified with a relative risk reduction of 29% for the primary endpoint (HR = 0.71; 95% CI, 0.56-0.9) on per-protocol analysis

There were no differences for adverse events between both groups and colchicine was well tolerated. However, patients assigned colchicine experienced greater rates of diarrhoea (9.7% vs. 8.9%; P = .35) and pneumonia (0.9% vs. 0.4%; P = .03). At 2 years, colchicine (18.4%) and placebo (18.7%) had similar drug discontinuation rates.

 

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