The need for wider and appropriate utilization of aspirin and statins in the treatment and prevention of cardiovascular disease

There is an increasing burden of occlusive cardiovascular disease (CVD) in developed, as well as in developing, countries. In fact, the WHO has projected that CVD will become the leading cause of death in the world in the next 10 years. The proximate cause of virtually all occlusive vascular events is thrombosis and the principal underlying cause is atherosclerosis. Aspirin, which inhibits platelet-dependent cyclooxygenase for the entire life of the platelet, has clinically important antithrombotic effects. Statins, which principally decrease low-density lipoprotein cholesterol, triglycerides and increase high-density lipoprotein cholesterol, have clinically important antiatherogenic effects. In secondary prevention, in a wide range of patients who have survived a prior myocardial infarction (MI), occlusive stroke, transient ischemic attack, as well as other high-risk conditions, long-term use of aspirin confers statistically significant and clinically important reductions in MI, stroke and CVD death. In addition, aspirin confers similar benefits when administered during acute MI or acute occlusive stroke. In primary prevention, aspirin confers a statistically significant and clinically important reduction in risk of a first MI but the data on stroke and CVD death remain inconclusive, so aspirin should be prescribed on an individual basis by the healthcare provider who weighs this clear benefit against long-term side effects. In a meta-analysis of 14 randomized trials of 90,056 subjects treated for 5 years, statins confer statistically significant and clinically important reductions in MI, stroke, CVD death and total mortality. In a meta-analysis of randomized trials of statins, in which aspirin was used in varying frequencies, the combination of aspirin and statins conferred greater clinical benefits than either agent alone on MI, occlusive stroke and CVD death. At present, the wider and more appropriate use of aspirin and statins will reduce premature MI, stroke and CVD death.     

Hypothesis: atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease

The results of numerous long-term, randomized trials show that statins significantly decrease the risks of myocardial infarction, stroke, and vascular death as well as total mortality. The benefits of statins on cardiovascular disease in patients who are not experiencing acute coronary syndromes generally become apparent only after about 2 years. In contrast, atorvastatin conferred an early clinical benefit in the lipid-lowering arm of the long-term Anglo Scandinavian Cardiac Outcomes Trial as well as early benefit on progression of atherosclerosis in the Reversal of Atherosclerosis with Aggressive Lipid Lowering trial. An unexpected finding at baseline in the prospective Interaction of Atorvastatin and Clopidogrel Study was that patients on atorvastatin had significantly decreased platelet activity compared with either patients on other statins or those taking no statins. Atorvastatin has protective effects against membrane lipid peroxidation at pharmacologic concentrations. These and other considerations contribute to the hypothesis that atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease.     

Efficacy of aspirin for secondary prevention in patients with peripheral artery disease

Evaluation of: Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 301, 1909–1919 (2009).

Aspirin decreases the risk of cardiovascular events in patients with prior coronary heart or cerebrovascular disease. The American College of Cardiology/American Heart Association guidelines recommend a low-dose aspirin regimen (75–325 mg/day) to reduce the risk of cardiovascular events in patients with peripheral artery disease (PAD). However, the effect of aspirin for secondary prevention in patients with PAD has not been well established. The paper under evaluation performed a meta-analysis of 18 trials to investigate the effect of aspirin on cardiovascular events (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) in patients with PAD. The results of this meta-analysis in a PAD cohort revealed that treatment with aspirin did not significantly reduce the combined end point of cardiovascular events; however, aspirin resulted in a significant reduction in the incidence of nonfatal stroke. This analysis raises a number of questions regarding the overall efficacy of aspirin in PAD and what should be the optimal antiplatelet therapy in patients with PAD: aspirin, clopidogrel or perhaps a combination of aspirin and clopidogrel.     

Potential nontraditional applications of statins

OBJECTIVE: To review the current evidence for use of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) in nontraditional lipid-related applications, including acute coronary syndromes, peripheral arterial disease, stroke, and renal disease, and to describe ongoing trials evaluating the role of statins in these conditions. DATA SOURCES: Clinical literature was identified by a MEDLINE search (1990-November 2002) using >/=1 of the following search terms: acute coronary syndrome(s), angina pectoris, atherosclerosis, atorvastatin, clinical trials, diabetes mellitus, end-stage renal disease, fluvastatin, lovastatin, myocardial infarction, peripheral arterial disease, pravastatin, simvastatin, statins, and stroke. Treatment guidelines issued by professional and governmental organizations, such as the American Diabetes Association, American Heart Association, National Cholesterol Education Program, National Kidney Foundation, and National Stroke Foundation, were reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles identified from the data sources were included if they pertained to the conditions described in the objectives and provided unique information concerning use of statins. DATA SYNTHESIS: Substantial evidence exists for the use of statins in acute coronary syndromes. Meta-analyses of data from major clinical trials indicate that statins prevent first and recurrent stroke, and large-scale trials are underway to evaluate the efficacy of statins in this setting. Accumulating evidence suggests that statins may be beneficial in reducing the morbidity and mortality associated with peripheral arterial disease and end-stage renal disease, and results from ongoing trials may confirm these benefits. Statins may also have a future role in amelioration of other conditions associated with atherosclerosis, such as diabetes mellitus. CONCLUSIONS: A large body of evidence supports the evaluation of statins in clinical settings beyond primary and secondary prevention of morbidity and mortality associated with coronary atherosclerosis.     

Dose of aspirin in the treatment and prevention of cardiovascular disease: current and future directions

In meta-analyses of randomized trials of aspirin among patients with prior occlusive vascular disease events (secondary prevention), doses from 75 mg to more than 1500 mg daily provide similar benefits on myocardial infarction, stroke, and cardiovascular death. In acute myocardial infarction and during acute occlusive stroke, a loading dose of 162.5 to 325 mg is necessary to achieve a rapid clinical antithrombotic effect. In primary prevention trials, predominantly among men, aspirin (75 mg daily to 325 mg on alternate days) reduced the risk of a first myocardial infarction. In a large-scale trial in women, aspirin (100 mg on alternate days) reduced risk of a first stroke. In subgroup analyses of women older than age 65, aspirin significantly reduced first myocardial infarction and ischemic stroke. Direct comparisons of higher doses may yield additional cardiovascular benefits. At present, daily doses of 75 to 325 mg aspirin are sufficient for long-term treatment and prevention of cardiovascular disease.     

Anti-platelet drugs (aspirin, ticlopidine, etc)

Previous clinical trials have shown that anti-platelet drugs, such as aspirin and ticlopidine, are approved for prevention of serious cardiovascular events in special populations who are at increased risk of cardiovascular events. Of these trials, the Antithrombotic Trialists' Collaboration (ATT) meta-analysis includes approximately 200,000 patients: Anti-platelet therapy was associated with a 34% reduction in the risk of nonfatal myocardial infarction, a 25% reduction in the risk of stroke, and a 15% reduction in the risk of vascular death. Also in patients with acute coronary syndrome (acute myocardial infarction and unstable angina), both aspirin and ticlopidine have been shown to prevent serious cardiovascular events.     

Effects of perioperative statins on patient outcomes after noncardiac surgery: a meta-analysis

Background: Cardiovascular complications are strongly correlated with a higher risk of mortality during follow-up after noncardiac surgery. However, controversy remains regarding whether perioperative administration of hydroxymethylglutaryl-CoA reductase inhibitors (statins) has a beneficial effect on patient outcomes.

Objective: We performed a meta-analysis to validate the hypothesis that perioperative statins improve patient outcomes after noncardiac surgery.

Methods: Electronic databases (PubMed, Web of Science, EMBASE, and the Cochrane Library) were searched for randomized controlled trials (RCTs) published up to 10 November 2017. RCTs were eligible for inclusion if they compared perioperative statin treatment with control treatment in patients scheduled for noncardiac surgery and reported data pertaining to clinical outcomes.

Results: Twelve RCTs involving 4707 patients (2371 in the perioperative statin group and 2336 in the control group) were ultimately included in this meta-analysis. The incidences of postoperative myocardial infarction, composite of death/myocardial infarction/stroke and new cases of atrial fibrillation were all lower in patients treated with statins than in control group patients, as shown by the fixed-effects model (odds ratio (OR)?=?0.460, 95% confidence interval (CI)?=?0.324–0.653, p?=?0 for myocardial infarction; OR?=?0.617, 95% CI?=?0.476–0.801, p?=?0 for composite of death/myocardial infarction/stroke; OR?=?0.406, 95% CI?=?0.247–0.666, p?=?0 for new atrial fibrillation). No significant differences in the incidences of stroke or transient ischemic attack, all-cause mortality and cardiovascular mortality were observed between the statin and control arms.

Conclusions: This meta-analysis supports the hypothesis that perioperative statins effectively reduce the incidences of postoperative myocardial infarction, composite of death/myocardial infarction/stroke and new cases of atrial fibrillation in patients undergoing noncardiac surgery.

• Key Messages

• Cardiovascular complications are strongly correlated with a higher risk of mortality during follow-up after noncardiac surgery.

• We performed a meta-analysis to confirm the hypothesis that perioperative statins improve patient outcomes after noncardiac surgery.

     

Cyclooxygenase-2 inhibitors and most traditional nonsteroidal anti-inflammatory drugs cause similar moderately increased risks of cardiovascular disease

Cyclooxygenase-2 inhibitors relieve pain from inflammatory conditions by decreasing the gastrointestinal side effects from traditional nonsteroidal anti-inflammatory drugs. Basic research provided plausible mechanisms and some observational epidemiological studies, case-control and cohort, indicated that patients prescribed with cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory drugs had increased risks for myocardial infarction and stroke. Because patients prescribed with cyclooxygenase-2 inhibitors were systematically different, uncontrolled and uncontrollable confounding by indication was as large as the observed risks. Thus, epidemiological studies or their meta-analyses could not discern whether, and if so, how much, the risks were real. A comprehensive meta-analysis of randomized trials indicated that cyclooxygenase-2 inhibitors increased the risk of vascular events by 42%, almost exclusively myocardial infarction, as did high-dose regimens of ibuprofen and diclofenac, but not naproxen. Individual clinical judgments and policy decisions should include cardiovascular disease and noncardiovascular disease risks including gastrointestinal side effects and clinical benefits including improved quality of life from less pain and disability.     

Statins and stroke prevention

Over the past decade, statins have been proved to significantly decrease coronary events in the primary and secondary prevention of coronary artery disease. Recent clinical trials have indicated that statins significantly reduce stroke risk in patients with vascular disease. A meta-analysis of randomized trials of statins in combination with other preventive strategies, involving 165,792 individuals, showed that each 1-mmol/l (39 mg/dl) decrease in LDL-cholesterol equates to a reduction in relative risk for stroke of 21.1 (95% CI: 6.3–33.5; p = 0.009). It is not known whether these findings might be due to the cholesterol-reduction effect of statins or to the pleiotropic effects of statins, such as improved endothelial function, decreased platelet aggregability and reduced vascular inflammation. In the secondary prevention of stroke, The Stroke Prevention by Aggressive Reduction of Cholesterol Levels study found that treatment with atorvastatin reduced the risk of recurrent cerebrovascular events in patients with recent stroke or transient ischemic attack but no history of heart disease.     

Pharmacologic treatment of hyperlipidemia

Pharmacologic treatment of hyperlipidemia in conjunction with therapeutic lifestyle changes can be used for both primary and secondary prevention of cardiovascular disease. Statins have the most convincing data for primary prevention, especially for higher risk patients. Therefore, risk stratification is essential. Statin therapy is also recommended for secondary prevention in all patients with known cardiovascular disease or the risk equivalent. High-dose statins should be initiated in patients with acute coronary syndrome. Omega-3 fatty acids may be a good alternative after myocardial infarction for patients who cannot tolerate statins. Fibrates and niacin have not been shown to reduce all-cause mortality in secondary prevention, but may be useful adjuncts when statins alone cannot adequately control lipid levels. Other cholesterol-lowering medications used for primary or secondary prevention of cardiovascular disease have not been shown to consistently improve patient-oriented outcomes. There is good evidence for using statins in the secondary prevention of stroke and peripheral arterial disease.     

Preventing ischemic stroke in the older adult

Stroke is a deadly and disabling disease that preferentially afflicts older adults. It shares common risk factors with myocardial infarction (MI), such as hypertension, diabetes, and hyperlipidemia. Blood pressure control, cholesterol reduction with statins, and glucose control reduce the risk for both stroke and MI. Additionally, management of atrial fibrillation with warfarin reduces stroke risk. Beyond risk factor reduction, antiplatelet therapy is an effective option for lowering the likelihood of stroke in at-risk patients. Among antiplatelet agents, aspirin has been shown effective for secondary stroke prevention as well as primary and secondary MI prevention; clopidogrel for secondary stroke and MI prevention; and both ticlodipine and dipyridamole for secondary stroke prevention. Combining antiplatelet agents is rational. Carotid endarterectomy should be considered for stroke prevention in patients with ischemic symptoms; for patients with asymptomatic stenosis, potential benefit must be balanced against surgical risk.     

Sea Change for Marine Omega-3s: Randomized Trials Show Fish Oil Reduces Cardiovascular Events

Recently, 3 large randomized controlled trials (RCTs) have assessed the effects of supplementation with marine omega-3 fatty acids on the occurrence of cardiovascular disease (CVD) events. We reviewed this evidence and considered it in the context of the large and growing body of data on the CV health effects of marine omega-3s. One RCT examining 8179 patients, most with coronary heart disease (CHD), reported that 4 grams/day of a highly purified omega-3 product containing eicosapentaenoic acid (EPA) reduced the risk for major adverse CV events by 25% (P<.001). Two other recent RCTs in primary prevention populations showed that approximately 1 gram/day of purified fish oil containing 840 mg/day of EPA and docosahexaenoic acid (DHA) significantly reduced risks of CHD and CV death, especially in individuals who did not consume fish and seafood frequently. The American Heart Association (AHA) continues to emphasize the importance of marine omega-3s as a nutrient for potentially reducing risks of congestive heart failure, CHD, ischemic stroke, and sudden cardiac death. Marine omega-3s should be used in high doses for patients with CHD on statins who have elevated triglycerides and at about 1 gram/day for primary prevention for individuals who do not consume at least 1.5 fish or seafood meals per week.     

Secondary stroke prevention

Stroke is the most common life-threatening neurological disorder. Based on limited acute therapies, clinicians have opted to focus on preventive strategies to limit its recurrence. Targets for prevention include modifiable risk factors such as hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, obesity, alcohol use, and physical inactivity among others. The American Stroke Association and American Heart Association guideline for the secondary prevention of stroke published in 2006 provides comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of stroke or transient ischemic attack. This guideline helps healthcare providers who have arrived at a potential explanation of the cause of stroke in an individual patient to select therapies that reduce the risk of recurrent events and other vascular events. The purpose of this review is to highlight the recently published American Stroke Association/American Heart Association guidelines for the secondary prevention of stroke.     

Lipid-lowering drug use and cardiovascular events after myocardial infarction

BACKGROUND: The benefits of lipid-lowering drug treatment for the secondary prevention of coronary heart disease have been well established by randomized, controlled trials. Nonetheless, the risk of events has not been compared directly for inhibitors of hydroxymethylglutaryl coenzyme A reductase (statins) and non-statin lipid-lowering drugs. Further, it remains uncertain whether patients in usual practice who are treated with lipid-lowering drugs after myocardial infarction (MI) gain a similar benefit with regard to the risk of cardiovascular events compared with patients in randomized, controlled trials. OBJECTIVE: To assess the association between lipid-lowering drug therapies in usual clinical practice and the risk of cardiovascular events in patients with a first MI who were discharged alive from the hospital. METHODS: An inception-cohort study was performed among 1956 enrollees of Group Health Cooperative who sustained an incident MI between July 1986 and December 1996 and survived for at least 6 months after hospitalization. Subjects with untreated low-density-lipoprotein cholesterol concentrations > 130 mg/dL or untreated total cholesterol concentrations >200 mg/dL were included. The median duration of follow-up after the first MI was 3.3 years. Medical record review was used to collect information on cardiovascular risk factors. Computerized pharmacy records were used to assess antihyperlipidemic drug use during the first 6 months after hospitalization. RESULTS: Compared with 1263 subjects who did not receive lipid-lowering drug treatment, 373 subjects who received statins had a lower risk of recurrent coronary events (relative risk [RR] 0.59; 95% CI 0.39 to 0.89), stroke (RR 0.82; 95% CI 0.35 to 1.95), atherosclerotic cardiovascular mortality (RR 0.49; 95% CI 0.21 to 1.13), and any atherosclerotic cardiovascular event (RR 0.63; 95% CI 0.40 to 0.98). Among 320 subjects who used non-statin drug therapies, the RRs were 0.66 (95% CI 0.45 to 0.97) for recurrent coronary events, 0.95 (95% CI 0.46 to 1.95) for stroke, 0.68 (95% CI 0.35 to 1.32) for cardiovascular mortality, and 0.77 (95% CI 0.53 to 1.11) for any atherosclerotic cardiovascular event, compared with untreated hyperlipidemic patients. CONCLUSIONS: In this study of MI survivors, the use of lipid-lowering drug therapies after hospitalization was associated with a reduced risk of cardiovascular events. These results emphasize the importance of lipid-lowering drug treatment in patients with hyperlipidemia who survive a first MI.     

Inhaled anticholinergics and the long-term treatment of chronic obstructive pulmonary disease: Weighing benefits and risks

A meta-analysis recently published in the Journal of the American Medical Association found an increased risk of nonfatal myocardial infarction, stroke, and cardiovascular death associated with inhaled anticholinergic use in patients with chronic obstructive pulmonary disease (COPD); however, inherent limitations in the meta-analysis and contradictory results from other studies cast uncertainty onto its conclusions. For example, the Understanding Potential Long-term Impacts on Function with Tiotropium trial, a large, prospective, 4-year outcome study in nearly 6000 patients with COPD, did not demonstrate an increase in cardiovascular events with anticholinergic therapy. Until more data are available, clinicians should always carefully weigh safety and efficacy data and help patients make informed decisions about their COPD care.     

Update on vitamin supplements for the prevention of coronary disease and stroke

Dietary antioxidants and folic acid may play a role in the pathophysiology of coronary disease and stroke. We review patient-oriented evidence on the effectiveness of supplementation with antioxidants and/or folic acid in the prevention of myocardial infarction and stroke. Observational data suggest cardiovascular benefit of vitamin E supplementation, but results of controlled clinical trials are inconsistent regarding the effect on nonfatal myocardial infarction. Moreover, studies have not shown a protective effect of vitamin E against fatal myocardial infarction and have not addressed stroke. For vitamin C and folic acid supplementation, observational data are inconsistent and controlled clinical trials are lacking. Thus, the available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of myocardial infarction or stroke. The evidence argues against the use of beta carotene supplements for this purpose. The costs and risks associated with these supplements are low, however, and physicians may choose to recommend vitamin E, folate and/or vitamin C supplementation pending conclusive evidence from clinical trials.     

Carotid revascularization for prevention of stroke: carotid endarterectomy and carotid artery stenting

Carotid endarterectomy (CEA) has been used for the past several decades in patients with carotid occlusive disease. Large randomized controlled trials have documented that CEA is a highly effective stroke preventive among patients with carotid stenosis and recent transient ischemic attack or cerebral infarction. In asymptomatic patients with carotid stenosis, clinical trial data suggest that the degree of stroke prevention from CEA is less than among symptomatic patients. However, otherwise healthy men and women with an asymptomatic carotid stenosis of 60% or greater have a lower risk of future cerebral infarction, including disabling cerebral infarction, if treated with CEA compared with those treated with medical management alone. More recently, carotid artery stenting has been performed Increasingly for patients with carotid occlusive disease. As technology has improved, procedural risks have declined and are approaching those reported for CEA. The benefits and durability of CEA compared with carotid artery stenting are still unclear and are being studied in ongoing randomized controlled trials.     

Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial

OBJECTIVE: Diabetes, a major health problem worldwide, increases the risk of cardiovascular disease and its associated mortality: The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that cholesterol-lowering treatment with pravastatin reduced mortality and coronary heart disease (CHD) events in 9014 patients aged 31-75 years with CHD and total cholesterol 4.0-7.0 mmol/l. We measured the effects of pravastatin therapy, 40 mg/day over 6.0 years, on the risk of CHD death or nonfatal myocardial infarction and other cardiovascular outcomes in 1,077 LIPID patients with diabetes and 940 patients with impaired fasting glucose (IFG). RESULTS: In patients allocated to placebo, the risk of a major CHD event was 61% higher in patients with diabetes and 23% higher in the IFG group than in patients with normal fasting glucose, and the risk of any cardiovascular event was 37% higher in the diabetic group and 19% higher in the IFG group. Pravastatin therapy reduced the risk of a major CHD event overall from 15.9 to 12.3% (relative risk reduction [RRR] 24%, P < 0.001) and from 23.4 to 19.6% in the diabetic group (19%, P = 0.11); in the diabetic group, the reduction was not significantly different from the reductions in the other groups. Pravastatin reduced the risk of any cardiovascular event from 52.7 to 45.2% (21%, P < 0.008) in patients with diabetes and from 45.7 to 37.1% (26%, P = 0.003) in the IFG group. Pravastatin reduced the risk of stroke from 9.9 to 6.3% in the diabetic group (RRR 39%, CI 7-61%, P = 0.02) and from 5.4 to 3.4% in the IFG group (RRR 42%, CI -9 to 69%, P = 0.09). Pravastatin did not reduce the incidence of diabetes. Over 6 years, pravastatin therapy prevented one major CHD event (CHD death or nonfatal myocardial infarction) in 23 patients with IFG and 18 patients with diabetes. A meta-analysis of other major trials confirmed the high absolute risks of diabetes and IFG and the absolute benefits of statin therapy in these patients. CONCLUSIONS: Cholesterol-lowering treatment with pravastatin therapy prevents cardiovascular events, including stroke, in patients with diabetes or IFG and established CHD.     

Secondary prevention in stroke: a primary rehabilitation concern

Stroke is a recurrent disease. Approximately one in four hospital admissions for stroke is due to recurrence; patients who have had a stroke are five times as likely to have another stroke as matched controls without stroke. While attention has been focused on the problem of primary prevention of stroke in patients with hypertension and/or transient ischemic attacks, the important problem of preventing stroke recurrence has been addressed to only a limited extent. In this paper, we review known risk factors for recurrence as well as possible medical and surgical approaches to reducing the probability of stroke recurrence. At this point, there appears to be no intervention which has unequivocal proven benefit, although several large-scale clinical trials are now in progress. Further clinical research on this problem is needed. An opportune time to institute and conduct research on interventions directed toward reducing the risk of stroke recurrence may be during the subacute recovery phase while patients are engaged in a program of comprehensive medical rehabilitation. Prevention of recurrent stroke and related vascular events for which stroke patients have increased risk (eg, myocardial infarction) should be of major concern in stroke rehabilitation practice.     

Incorporation of PCSK9 inhibitors into prevention of atherosclerotic cardiovascular disease

Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has become recently more complex than ever, leaving the clinicians perplexed with outdated guidelines and emerging evidence about new LDL-C lowering therapies. 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have focused on high intensity statin therapy for specific groups of patients, while abandoning long established LDL-C goals, a strategy which no longer seems valid. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have emerged as the add-on therapy on top of statins and/or ezetimibe for the treatment of hypercholesterolemia and ASCVD prevention. In several clinical trials, PCSK9 inhibitors have demonstrated their safety and robust LDL-C-lowering power. One completed cardiovascular (CV) outcomes trial (FOURIER; Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk) has demonstrated that PCSK9 inhibition reduces rates of CV death as well as non-fatal stroke and MI, while another major CV outcome trial is under way (ODYSSEY-OUTCOMES). Several trials studying CV benefits of novel LDL-C-lowering therapies are also being conducted. Prompt revision of ACC/AHA guidelines is necessary. In the meantime, physicians need to use clinical judgment integrating the most recent evidence into their practice.