Cost-Effectiveness of Lipid-Lowering Therapies for Cardiovascular Prevention in Germany

Purpose Novel pharmaceutical treatments reducing cardiovascular events in dyslipidaemia patients must demonstrate clinical efficacy and cost-effectiveness to promote long-term adoption by patients, physicians, and insurers. Objective To assess the cost-effectiveness of statin monotherapy compared to additive lipid-lowering therapies for primary and secondary cardiovascular prevention from the perspective of Germany’s healthcare system. Methods Transition probabilities and hazard ratios were derived from cardiovascular outcome trials for statin combinations with icosapent ethyl (REDUCE-IT), evolocumab (FOURIER), alirocumab (ODYSSEY), ezetimibe (IMPROVE-IT), and fibrate (ACCORD). Costs and utilities were retrieved from previous literature. The incidence of major adverse cardiovascular events was simulated with a Markov cohort model. The main outcomes were the incremental cost-effectiveness ratios (ICER) per quality adjusted life year (QALY) gained. Results For primary prevention, the addition of icosapent ethyl to statin generated 0.81 QALY and €14,732 costs (ICER: 18,133), whereas fibrates yielded 0.63 QALY and € − 10,516 costs (ICER: − 16,632). For secondary prevention, the addition of ezetimibe to statin provided 0.61 QALY at savings of € − 5,796 (ICER: − 9,555) and icosapent ethyl yielded 0.99 QALY and €14,333 costs (ICER: 14,485). PCSK9 inhibitors offered 0.55 and 0.87 QALY at costs of €62,722 and €87,002 for evolocumab (ICER: 114,639) and alirocumab (ICER: 100,532), respectively. A 95% probability of cost-effectiveness was surpassed at €20,000 for icosapent ethyl (primary and secondary prevention), €119,000 for alirocumab, and €149,000 for evolocumab. Conclusions For primary cardiovascular prevention, a combination therapy of icosapent ethyl plus statin is a cost-effective use of resources compared to statin monotherapy. For secondary prevention, icosapent ethyl, ezetimibe, evolocumab, and alirocumab increase patient benefit at different economic costs.

The Role of Lipid-Lowering Treatment in the Secondary Prevention of Ischemic Stroke

Dyslipidemia is a major modifiable risk factor for ischemic stroke. Treatment with statins reduces the incidence of recurrent ischemic stroke and also reduces coronary events in patients with a history of ischemic stroke. Therefore, statins represent an important component of secondary prevention of ischemic stroke. In patients who do not achieve low-density lipoprotein cholesterol (LDL-C) targets despite treatment with the maximal tolerated dose of a potent statin, ezetimibe should be added to their lipid-lowering treatment and also appears to reduce the risk of cardiovascular events. Selected patients who do not achieve LDL-C targets despite statin/ezetimibe combination are candidates for receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Finally, it appears that adding icosapent ethyl might also reduce cardiovascular morbidity in patients who have achieved LDL-C targets but have persistently elevated triglyceride levels.

Secondary Prevention of Cardiovascular Disease in Women: Closing the Gap

Cardiovascular disease (CVD) remains the leading cause of death in women globally. Younger women (<55 years of age) who experience MI are less likely to receive guideline-directed medical therapy (GDMT), have a greater likelihood of readmission and have higher rates of mortality than similarly aged men. Women have been under-represented in CVD clinical trials, which limits the generalisability of results into practice. Available evidence indicates that women derive a similar benefit as men from secondary prevention pharmacological therapies, such as statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, icosapent ethyl, antiplatelet therapy, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. Women are less likely to be enrolled in cardiac rehabilitation programs than men. Mitigating risk and improving outcomes is dependent on proper identification of CVD in women, using appropriate GDMT and continuing to promote lifestyle modifications. Future research directed at advancing our understanding of CVD in women will allow us to further develop and tailor CVD guidelines appropriate by sex and to close the gap between diagnoses, treatment and mortality.

Treatment of Hypertriglyceridemia: A Review of Therapies in the Pipeline

Background The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines and 2021 ACC Expert Consensus Decision Pathway recommend nonpharmacological interventions and initiation of statin therapy for patients with moderate hypertriglyceridemia and addition of fibrates or omega-3 fatty acids in severe hypertriglyceridemia. Although the association between triglyceride (TG) lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction remains controversial, patients with hypertriglyceridemia may represent a subgroup that require additional therapy to further reduce residual ASCVD risk. Moreover, medications that target novel pathways could provide alternative options for patients who are intolerant of existing therapies or doses needed to provide adequate triglyceride lowering. Objective: Assess recent evidence for TG-lowering agents including omega-3 fatty acid-based therapies, PPARα modulators, apoC-III mRNA antisense inhibitors, angiopoietin-like 3 (ANGPTL3) antibodies, and herbal supplements. Methods: A literature search was performed using PubMed with hypertriglyceridemia specified as a MeSH term or included in the title or abstract of the article along with each individual agent. For inclusion, trials needed to have a primary or secondary outcome of TG levels or TG lowering. Conclusion: Currently, the only US Food and Drug Administration approved medication for CV risk reduction in patients with hypertriglyceridemia is icosapent ethyl. Results from phase 3 trials for CaPre, pemafibrate, and volanesorsen as well as additional evidence for pipeline pharmacotherapies with novel mechanisms of action (e.g., ApoC-III mRNA antisense inhibitors and ANGPTL3 antibodies) will help to guide future pharmacotherapy considerations for patients with hypertriglyceridemia.

Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients with Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL

Background: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. Methods: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) was a multicenter, double-blind, placebo-controlled trial that randomized statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and one additional risk factor to treatment with icosapent ethyl (4 grams daily) or placebo. Patients from REDUCE-IT were categorized by prespecified eGFR categories to analyze the effect of icosapent ethyl on the primary endpoint (composite of cardiovascular [CV] death, nonfatal myocardial infarction nonfatal stroke, coronary revascularization, or unstable angina) and key secondary endpoint (a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke). Results: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL/min/1.73m 2 (range: 17 to 123 mL/min/1.73m 2 ). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and secondary composite endpoints across baseline eGFR categories. Patients with eGFR<60 mL/min/1.73m 2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite endpoint (icosapent ethyl versus placebo, 21.8% versus 28.9%, hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.59-0.85, P=0.0002) and key secondary composite endpoints (16.8% versus 22.5%, HR 0.71, 95% CI 0.57-0.88, p=0.001). The numerical reduction in CV death was greatest in the eGFR <60 mL/min/1.73m 2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR 0.70, 95% CI 0.51-0.95, P=0.02). While patients with eGFR <60 mL/min/1.73m 2 treated with icosapent ethyl had the highest numerical rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42, 95% CI 0.86-2.32, P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR 1.40, 95% CI 0.90-2.18, P=0.13), hazard ratios for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter = 0.92; P-interaction for serious bleeding = 0.76). Conclusions: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01492361

Icosapent Ethyl Reduces Ischemic Events in Patients with a History of Prior Coronary Artery Bypass Grafting: REDUCE-IT CABG

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk following coronary artery bypass grafting (CABG) surgery. Methods: In the multicenter, placebo-controlled, double-blind trial REDUCE-IT, statin-treated patients with controlled low-density lipoprotein cholesterol (LDL-C) and mild to moderate hypertriglyceridemia were randomized to 4g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint (cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The present analysis reports on the subgroup of patients from the trial with a history of CABG. Results: Of the 8,179 patients randomized in REDUCE-IT, a total of 1,837 (22.5%) had a history of CABG, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.92; P=0.004), in the key secondary endpoint (HR, 0.69; 95% CI, 0.56-0.87; P=0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64; 95% CI, 0.50-0.81; P=0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%-10.2%) in first events, with a number needed to treat of 16 (95% CI, 10-44) over a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs. 3.1%; P=0.03) and a non-significant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of CABG, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events.

Women and Diabetes: Preventing Heart Disease in a New Era of Therapies

Despite major advances in cardiovascular research over the past decade, women with type 2 diabetes have a high risk of cardiovascular events. Several factors contribute to the poor prognosis for women, including higher levels of frailty and comorbidities, but their cardiovascular risk is underestimated and there is suboptimal implementation and uptitration of new evidence-based therapies, leading to high morbidity and mortality. Recent studies highlight the need for better management of diabetes in women that can be pursued and achieved in light of recent results from randomised controlled trials demonstrating evidence of the benefits of new therapeutic strategies in improving cardiovascular outcomes and quality of life of women covering the entire cardiovascular continuum. This review critically discusses the multiple benefits for women of new pharmacological treatments, such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter type 2 inhibitors (SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, icosapent ethyl and bempedoic acid in preventing cardiovascular events, and treatments, such as angiotensin receptor neprilysin inhibitors, SGLT2i, vericiguat and omecamtiv mecarbil, for preventing heart failure.