RECENT LANDMARK TRIALS
Year : 2018 | Volume
: 7 | Issue : 2 | Page : 79--83
Recent trials exploring newer approaches for incremental reduction in cardiovascular risk
Showkat Hussain Bhat, Abinav Jain, Rahul Mehrotra
Department of Non-Invasive Cardiology, Max Super Speciality Hospital, New Delhi, India
Dr. Rahul Mehrotra
Max Super Speciality Hospital, Saket (East Block), New Delhi
|How to cite this article:|
Bhat SH, Jain A, Mehrotra R. Recent trials exploring newer approaches for incremental reduction in cardiovascular risk.J Clin Prev Cardiol 2018;7:79-83
|How to cite this URL:|
Bhat SH, Jain A, Mehrotra R. Recent trials exploring newer approaches for incremental reduction in cardiovascular risk. J Clin Prev Cardiol [serial online] 2018 [cited 2020 Jul 7 ];7:79-83
Available from: http://www.jcpconline.org/text.asp?2018/7/2/79/228337
Anti-Inflammatory Therapy With Canakinumab for Atherosclerotic Disease
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C; for the CANTOS Trial Group, et al. N Engl J Med 2017;377:1119-31.
Background: Inflammation has long been proposed as a mechanism involved in atherosclerotic disease process. Accordingly, reducing the level of inflammation may help in reducing the risk of cardiovascular (CV) disease independent of other risk factors. Statin trials have shown that statins lower cholesterol along with reducing inflammatory markers, resulting in significant CV risk reduction. There is no evidence that reduction in inflammation alone, without lipid lowering will result in CV risk reduction.
Methods: This was a randomized, double-blind trial of canakinumab (a fully human monoclonal antibody targeting interleukin-1β), involving 10,061 patients with a history of previous myocardial infarction and a high-sensitivity C-reactive protein level (hs-CRP) of ≥2 mg/L. The trial compared three doses of canakinumab (50, 150, and 300 mg administered subcutaneously every 3 months) with placebo. The primary efficacy end point was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or CV death in a time-to-event analysis. The trial also had two key secondary efficacy end points. The first key secondary end point included the components of the primary end point as well as hospitalization for unstable angina that led to urgent revascularization. The second key secondary end point was the incidence of new-onset type 2 diabetes among patients with prediabetes.
Results: Initially, patients were randomly assigned in a 1:1:1 ratio to receive placebo, canakinumab at a dose of 150 mg or canakinumab at a dose of 300 mg. After the enrollment of 741 patients, a 50 mg dose of canakinumab was added at the request of a regulatory agency, and the randomization ratio was adjusted accordingly, to achieve a final randomization ratio of 1.5 (placebo group):1:1:1. At 48 months, the median reduction from baseline in the hs-CRP level was 26% greater in the group that received the 50 mg dose of canakinumab, 37% greater in the 150 mg group, and 41% greater in the 300 mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence of primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 in the 50 mg group, 3.86 in the 150 mg group, and 3.90 events per 100 person-years in the 300 mg group. The 150 mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina, leading to urgent revascularization (hazard ratio [HR] vs. placebo, 0.83; 95% confidence interval [CI]: 0.73–0.95; P = 0.005). There was no significant difference in all-cause mortality (HR for all canakinumab doses vs. placebo, 0.94; 95% CI: 0.83–1.06; P = 0.31). However, canakinumab was associated with a higher incidence of fatal infection compared to placebo.
Conclusions: Canakinumab significantly reduced hs-CRP levels from baseline, as compared to placebo, without reducing the low-density lipoprotein (LDL) cholesterol level, and the 150 mg dose resulted in a significantly lower incidence of recurrent CV events compared to placebo.
The CANTOS trial is a landmark study because it tested for the first time the hypothesis that blocking an important component of the inflammatory cascade (interleukin-1β) involved in atherosclerotic heart disease will translate into an improved outcome. Interleukin-1β is a cytokine that is central to the inflammatory response which drives the interleukin-6 signaling pathway. The pro-inflammatory cytokine interleukin-1β plays multiple roles in the development of atherothrombotic plaque including the induction of procoagulant activity, the promotion of monocyte and leukocyte adhesion to vascular endothelial cells, and the growth of vascular smooth muscle cells.
Canakinumab, a fully human monoclonal antibody targeting interleukin-1β, has anti-inflammatory effects and has been approved for clinical use in rheumatologic disorders. Although the 50 mg dose of canakinumab did not have a significant effect on the primary CV end point as compared with placebo, patients in the 150 mg group had a risk of the primary end point that was 15% lower than in the placebo group (3.86 vs. 4.50 events per 100 person-years) and a risk of the key secondary CV end point that was 17% lower than that in the placebo group (4.29 vs. 5.13 events per 100 person-years). The P values for both end points met the prespecified multiplicity-adjusted thresholds for statistical significance.
Despite the fact that no significant reduction in cholesterol levels occurred in this trial, the magnitude of effect on CV events with canakinumab (given every 3 months) was similar to that associated with monoclonal antibodies targeting proprotein convertase subtilisin–kexin type 9 (PCSK9; given every 2–4 weeks). Interestingly, cancer mortality was also significantly lower among the patients assigned to receive canakinumab than among those in the placebo group. However, the significantly higher incidence of fatal infection and sepsis was noted with canakinumab than with placebo, as well as a reduction in platelet counts with no increase in bleeding risk which will need to be carefully looked into.
Rivaroxaban With or Without Aspirin in Stable Cardiovascular Disease
Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O; for the COMPASS Investigators, et al. N Engl J Med 2017;377:1319-30.
Background: Despite the use of effective secondary prevention strategies, approximately, 5%–10% of patients with CV disease have recurrent events each year. This trial tested the role of newer oral anticoagulant rivaroxaban (direct factor Xa inhibitor) alone or in combination with aspirin for secondary prevention in patients with stable CV disease.
Methods: This was a multicenter, double-blind, randomized trial involving patients with stable atherosclerotic vascular disease. Patients with coronary artery disease, peripheral artery disease, or both were included in the study. Patients with coronary artery disease <65 years of age required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional risk factors (current smoking, diabetes mellitus [DM], an estimated glomerular filtration rate [GFR] <60 ml/min, heart failure, or nonlacunar ischemic stroke ≥1 month earlier). People with high bleeding risk, a recent stroke, severe heart failure, estimated GFR <15 ml/min, the use of dual antiplatelet therapy, anticoagulation, or other antithrombotic therapy and non-CV conditions deemed by the investigator to be associated with a poor prognosis were excluded from the trial. A total of 27,395 participants were randomly assigned in a 1:1:1 ratio to receive either rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily (9152 patients) or rivaroxaban alone 5 mg twice daily (with an aspirin-matched placebo once daily (9117 patients), or aspirin alone 100 mg once daily (with a rivaroxaban-matched placebo twice daily) with 9126 patients. Before randomization, patients entered a run-in phase during which they received a rivaroxaban-matched placebo twice daily and aspirin 100 mg daily. Around 2300 participants were excluded from the trial after the run-in phase. The primary efficacy outcome was the composite of CV death, stroke, or myocardial infarction, and the main safety outcome was a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding and included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization. Patients were followed up for a median period of 23 months.
Results: Baseline characteristics were similar among the groups. Seventy-eight percent were men, 75% had hypertension, and 90% had a history of coronary artery disease with 62% having a previous myocardial infarction. Ninety percent were on statins and 71% were taking ACE inhibitor or ARB. The primary end point occurred in 4.1% of patients in the rivaroxaban plus aspirin group compared to 5.4% patients in the aspirin alone group (95% CI: 0.66–0.86; P < 0.001). On the other hand, primary efficacy end point was seen in 4.9% in rivaroxaban alone group versus 5.4% in the aspirin alone group (95% CI 0.79–1.03; P = 0.12). The clinical benefits in the efficacy outcomes were offset by an increase in bleeding in the rivaroxaban groups (with or without aspirin) as compared to aspirin alone. Major bleeding as defined by the modified ISTH criteria was seen in 3.1% patients in the rivaroxaban plus aspirin group versus 2.8% in the rivaroxaban only group versus 1.9% in the aspirin alone group. However, nonfatal symptomatic intracranial hemorrhage was seen in 0.2% versus 0.4% and 0.2% patients, respectively. All-cause mortality occurred in 3.4% versus 4% and 4.1% patients, respectively, in the three groups (P = 0.67). The net-clinical-benefit outcome which comprised of CV death, stroke, nonfatal MI, fatal bleeding, or symptomatic bleeding into critical organs was significantly lower with rivaroxaban plus aspirin group and occurred in 4.7% versus 5.9% in the aspirin alone group (HR: 0.80 [95% CI 0.70–0.91] P < 0.001), whereas it was not significantly lower in the rivaroxaban alone group, 5.5% versus in aspirin alone group 5.9% (HR 0.94 [95% CI 0.84–1.07] P = 0.36).
Conclusions: In patients with stable CV disease, this trial compared the role of three regimens for secondary prevention of thrombotic events and found that risk of major adverse CV events were significantly reduced with a combination of rivaroxaban (2.5 mg twice daily) plus aspirin than with aspirin (100 mg once daily) alone although the risk of major bleeding was significantly higher with the two-drug combination. Rivaroxaban (5 mg twice daily) alone also did not result in a significantly lower risk of major adverse CV events compared to aspirin alone and resulted in a significantly higher risk of major bleeding.
Rivaroxaban is approved for reducing stroke risk in nonvalvular atrial fibrillation (AF) and in pulmonary embolism prophylaxis based on the results of earlier trials, but the dose strength is 15–20 mg once daily to twice daily. Subsequently, the ATLAS ACS2-TIMI 51 trial tested low-dose rivaroxaban in patients of acute coronary syndrome (ACS) in addition to antiplatelet therapy and other guideline-directed medical therapy. They found that rivaroxaban reduced the risk of the composite end point of death from CV causes, myocardial infarction, or stroke at the expense of increased bleeding complications.
The COMPASS investigators tested this low-dose rivaroxaban for secondary prevention with or without aspirin and found reduced thrombotic rates but again at the expense of increased bleeding risk.
At a mean follow-up of 23 months (after early termination of the trial due to achievement of the interim efficacy threshold), rivaroxaban plus aspirin was associated with a 1.3% absolute risk reduction in the primary outcome when compared to aspirin alone, whereas the relative risk reduction in the primary outcome was 24%.
Use of rivaroxaban plus aspirin was also associated with a 1.2% absolute increase in major bleeding compared to aspirin alone although the rate of intracranial hemorrhage was similar.
The majority of the bleeding sites were gastrointestinal. Of note, the modified ISTH bleeding by definition used in COMPASS was broader in scope and any bleeding that led to a presentation to an acute care facility or hospitalization was considered major.
A net-clinical-benefit outcome, attempting to incorporate both thrombotic and bleeding outcomes, demonstrated a 1.2% absolute reduction in events with the rivaroxaban plus aspirin group when compared to aspirin alone.
When rivaroxaban alone was compared to aspirin alone, essentially all thrombotic end points were similar, but with a higher bleeding risk associated with rivaroxaban use.
The limitations of the study are related to the early termination (possibly resulting in overestimation of the treatment effect and underestimation of bleeding) and the use of doses of rivaroxaban that are not currently approved by the Food and Drug Administration.
However, the COMPASS trial provides further evidence that the use of rivaroxaban in addition to background aspirin is effective in reducing thrombotic outcomes in patients with established atherosclerotic disease in comparison to aspirin alone but at a higher risk of major bleeding. Rivaroxaban alone was not superior to aspirin alone for this purpose but results in higher major bleeding.
Dual Antithrombotic Therapy With Dabigatran After Percutaneous Coronary Intervention in Atrial Fibrillation
Cannon CP, Bhatt DL, Oldgren J, Lip GY, Ellis SG, Kimura T, et al. N Engl J Med 2017;377:1513-24.
Background: In patients with nonvalvular AF undergoing percutaneous coronary intervention (PCI), the currently recommended therapy with warfarin plus dual antiplatelet agents is associated with significant risks of bleeding. With the evolution of newer oral anticoagulants such as dabigatran, combination of this drug with a P2Y12 inhibitor is likely to be a good alternative therapy for such patients.
Methods: This was a multicenter randomized trial which enrolled around 2700 patients with AF who had undergone PCI. The patients were randomized to either triple therapy – warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin, for 1–3 months, or two dual therapy groups with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin. In centers outside the USA, elderly patients (defined as >70 years for Japanese and >80 years in all other countries) were assigned to either 110 mg dual therapy group or triple therapy group as 150 mg dabigatran was not approved for this age group. Men and women who were at least 18 years of age were eligible for inclusion in the trial if they had nonvalvular AF and had successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 h for either an ACS or stable coronary artery disease. Key exclusion criteria were the presence of bioprosthetic or mechanical heart valves and severe renal insufficiency (creatinine clearance <30 ml/min). All the patients received either clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) for at least 12 months after randomization. The dose of warfarin was adjusted to ensure that the patients' prothrombin time (International Normalized Ratio) was within a range of 2.0–3.0. Follow-up was performed every 3 months. The primary end point was the occurrence of a major or clinically relevant nonmajor bleeding event as defined by the ISTH. The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.
Results: The incidence of the primary end point was 15.4% in the 110 mg dual-therapy group as compared with 26.9% in the triple therapy group (P < 0.001 for noninferiority; P < 0.001 for superiority) and 20.2% in the 150 mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group which did not include the elderly patients outside the USA (P < 0.001 for noninferiority). Furthermore, major bleeding as defined by TIMI grade was lower in both the dual-therapy groups as compared to the triple-therapy group (1.4% vs. 3.8% for 110 mg and 2.1% vs. 3.9% for 150 mg). Intracerebral hemorrhage was rare, but the incidence was lower in dual-therapy groups than in the triple-therapy groups. The incidence of the composite efficacy end point of thromboembolic events, death, or unplanned revascularization was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (P = 0.005 for noninferiority). It was 15.2% versus 13.4% in 110 mg group and 11.8% versus 12.8% in 150 mg group.
Conclusions: Among patients with AF who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual-therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.
Bleeding is a major source of morbidity and mortality in AF patients undergoing PCI. A balancing act between efficacy to reduce thromboembolism and the risk of bleeding is required. The current AHA/ACC guidelines suggest that, in patients with nonvalvular AF undergoing PCI, it is reasonable to maintain patients on oral anticoagulation (typically warfarin) and clopidogrel without aspirin. However, with the advent of newer anticoagulants, there is accumulating evidence supporting the use of these direct oral anticoagulants in patients with AF compared to warfarin in different scenarios.RE-DUAL PCI was a very well-designed trial in that it tested the recommended doses of dabigatran in AF with sufficient power to detect noninferiority for both primary and secondary end points. The trial once again established the safety of dabigatran in this very important subset of patients with AF undergoing PCI. It showed a clearly significant reduction in bleeding rates with the use of dabigatran in addition to a P2Y12 inhibitor as compared to triple-therapy group. For the primary end point of major or clinically relevant nonmajor bleeding, the difference in risk between the 110 mg dual-therapy group and the triple-therapy group was 48%, whereas it was 28% in the 150 mg dual-therapy group during approximately 1 year of treatment. In the secondary end point analysis, the investigators combined both the dual-therapy groups and compared with the triple therapy to achieve the power of 83.6%. When analyzed individually, the 110 mg dual-therapy group had increased occurrence of a major adverse cardiac event as compared with the triple therapy group which did not meet the criteria for noninferiority, whereas the 150 mg dual-therapy group met the criteria for noninferiority in both safety and efficacy end point when compared to the triple-therapy group. We seem to have found the missing piece in the puzzle of treating the patients of AF undergoing PCI, for the time being at least.
Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes: Results from Improve-It
Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalan R, Spinar J; for the IMPROVE-IT Investigators, et al. https://doi.org/10.1161/CIRCULATIONAHA.117.030950
Background: Ezetimibe, when added to simvastatin, reduces CV events following ACS was shown in the IMPROVE-IT study. In this subanalysis, diabetic patients were analyzed for outcomes.
Methods: Type 2 DM was a prespecified subgroup in the IMPROVE-IT trial which enrolled over 18,000 patients who had ACS with an LDL cholesterol (LDL-C) in the range of 50–125 mg/dL. The patients were randomized to receive either ezetimibe/simvastatin – 10/40 mg (E/S) or placebo/simvastatin – 40 mg (P/S). The primary composite endpoint was CV death, major coronary events, and stroke. Median follow-up was 7 years.
The present analysis compared the effects of ezetimibe among 4933 participants with DM enrolled in the IMPROVE-IT trial.
Results: The patients with diabetes were more often older, women, with prior MI/revascularization and presented more frequently with non-ST elevation ACS compared to nondiabetics. The median admission LDL-C was lower among patients with DM (89 vs. 97 mg/dL) as they were more likely to have been treated with statins. The primary composite end point occurred in 40% of diabetic subjects who were assigned to simvastatin/ezetimibe (n = 2459) compared with 45.5% of those treated with simvastatin alone (n = 2474) – a reduction of 14%. Greater reductions in LDL-C at 1 year were also seen among diabetic patients taking ezetimibe with simvastatin. LDL-C among these patients was reduced by 43 mg/dL compared with 23 mg/dL drop among patients taking simvastatin alone. The rates of myocardial infarction and stroke were also reduced among diabetic patients taking ezetimibe (E/S) by around 24% and 39%, respectively, compared to placebo. No significant differences were seen among nondiabetic subjects in the E/S group for these end points. When stratified further by age, patients ≥ 75 years had a 20% relative reduction in the primary end point regardless of diabetic status, whereas patients <75 years with diabetes demonstrated greater benefit than nondiabetics. Overall, patients with and without diabetes had similar rates of transaminase elevation and cancer; however, patients with DM were more likely to experience gallbladder- and muscle-related adverse events than those without DM.
Conclusions: The benefit of adding ezetimibe to statin appeared to be enhanced among patients with DM with no significant adverse effects. These findings support the use of intensive, combination lipid-lowering therapy in patients with DM to optimize CV outcomes.
IMPROVE-IT is the first trial to show that adding a nonstatin lipid-modifying agent (ezetimibe) in concert with a statin improves CV outcomes in addition to enhancing lipid-lowering effects. The reduction in LDL-C was associated with a decreased CV event rate. Ezetimibe acts locally at the brush border of small intestine by selectively inhibiting the cholesterol transport protein Niemann-Pick C1 protein L1, thereby preventing uptake of intestinal luminal micelles, which contain cholesterol, into the enterocytes. Ezetimibe not only lowers LDL-C but also reduces levels of other atherogenic particles such as remnant-like particle cholesterol, small dense-LDL-C, malondialdehyde modified-LDL, apolipoprotein B-48, and ratios of total cholesterol/high-density lipoprotein-cholesterol and ApoB/ApoA-I.
The significance of the IMPROVE-IT trial is twofold. First, it supports the theory of “lower is better” in terms of LDL-C levels and CV risk. Second, it is the first trial to show a significant reduction in CV events when ezetimibe is added to statin therapy, demonstrating a significant add-on effect of ezetimibe to statins in terms of both LDL-C reduction and reduction of CV events. In essence, it also supports the LDL hypothesis that lipid lowering improves CV outcomes. In IMPROVE-IT, patients with recent ACS randomized to ezetimibe versus placebo on the top of background simvastatin; it was found that patients with diabetes derived significantly greater relative and absolute benefit with the addition of ezetimibe relative to patients without diabetes. This enhanced benefit was driven by reductions of acute ischemic events including myocardial infarction and ischemic stroke in diabetics, while nondiabetic patients who were >75 years of age or had a high-risk score also significantly benefited from the addition of ezetimibe to simvastatin. The benefits of ezetimibe were achieved without an increase in safety events compared to placebo. A worthwhile drawback of this trial is that the effect size is small and the numbers needed to treat are high.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.