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Sajita Setia,1 Selwyn Sze-Wang Fung,2 David D Waters3 1Medical Affairs, Pfizer Pte Ltd, Singapore; 2Regional Medical Affairs, Pfizer Pte Ltd, Hong Kong; 3Department of Medicine, University of California, San Francisco, CA, USA Purpose: There is an unmet need for strategies to prevent atherosclerotic cardiovascular disease in Singapore. The main objective of this study was to investigate Singapore physicians’ response to the 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines for treatment of cholesterol and their impact on clinical practice. Methods: This survey was conducted in two stages, qualitative and quantitative. Physicians were initially screened on the basis of an initial screener questionnaire, and eligible physicians were then included in the study. Results: Qualitative (n=19) and quantitative (n=66) surveys were completed by eligible physicians from Singapore. Physicians were less familiar with the 2013 ACC/AHA guidelines (35%) as compared with the Singapore Ministry of Health (MoH) lipid guidelines 2006 (49%). Of the physicians whose opinion was sought on the ACC/AHA guidelines, more than 50% disagreed with the definition of high-, moderate-, and low-intensity statin therapy; recommendation of atorvastatin 40–80 mg and rosuvastatin 20–40 mg as medications for high-intensity statin therapy; and classification of individuals who would benefit from moderate- to high-intensity statin therapy. Most physicians assumed that Asians may be intolerant to high-intensity statin therapy. Conclusion: Although embracing the 2013 ACC/AHA guidelines in clinical practice is expected to provide better clinical care to patients, our study revealed high reluctance by physicians, especially in the use of high-dose statins. However, ACC/AHA guidelines can be easily adopted in Asia as there is a wealth of data available for atorvastatin in primary and secondary prevention of atherosclerotic cardiovascular disease with similar efficacy and safety profiles in the white and Asian populations. Keywords: cholesterol treatment, cardiovascular disease, statin therapy, CVD risk factors, LDL target levels

Waters DD, Alderman EL, Hsia J, et al. JAMA 2002;288:2432-2440. CONTEXT: Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, [...]

Cholesterol lowering with statins reduces coronary events in a primary-prevention setting and in patients with stable coronary disease. However, where the risk of a coronary event is highest, in the early months after an episode of unstable angina or non-Q-wave infarction, the effect of statin therapy has not been evaluated until recently. The lack of an early benefit in the 3 main statin trials in stable coronary disease may have discouraged this type of investigation. Yet, evidence suggests that intensive cholesterol lowering can rapidly influence several mechanisms intimately related to the pathogenesis of acute coronary syndromes; specifically, improvement in endothelial function, decreased propensity for platelet thrombus formation, and reduced inflammation. Furthermore, 3 nonrandomized, observational studies have recently reported an improved outcome in statin-treated compared with untreated patients after acute coronary syndromes. [ABSTRACT FROM AUTHOR]

To date, 5 major randomized, placebo-controlled statin trials--the Scandinavian Simvastatin Survival Study, West of Scotland Coronary Prevention Study, Cholesterol and Recurrent Events trial, Long-term Intervention with Pravastatin in Ischaemic Disease, and Air Force/Texas Coronary Atherosclerosis Prevention Study--have convincingly shown that total mortality and major coronary events can be significantly reduced by lowering levels of low-density lipoprotein cholesterol (LDL-C) with statin therapy. These results were achieved in a broad range of patients including those with and without a history of coronary artery disease and with elevated or average LDL-C levels. The results also support the large body of epidemiologic evidence demonstrating that the lower the cholesterol level, the lower the cardiovascular risk. Evidence now substantially supports the urgency of physicians to aggressively target the lowering of LDL-C levels for the primary and secondary prevention of coronary disease. [ABSTRACT FROM AUTHOR]

Subjects infected with human immunodeficiency virus (HIV) have increased risk for atherosclerosis. Carotid artery intima-media thickness (IMT) assessed using ultrasound and coronary artery calcium (CAC) detected using computed tomography predict cardiovascular risk in the general population; however, their usefulness and comparability in patients with HIV are less well defined. The purpose of this study was to compare IMT and CAC in the detection of atherosclerosis in subjects with HIV. CAC and IMT were measured in 253 HIV-infected and 58 uninfected adults. Associations among HIV-related factors, traditional risk factors, and CAC and IMT were evaluated. The distribution of IMT among subjects with and without CAC was compared. Among the patients with HIV, 37% had detectable CAC compared to 28% of controls (p = 0.19); 16% of the patients with HIV had CAC >100 compared to 5% of controls (p = 0.03). With either detectable or undetectable CAC, HIV-infected subjects had higher IMT compared to controls (1.02 ± 0.34 vs 0.78 ± 0.12 mm, p <0.0001), even after adjustment for traditional risk factors. Among those with undetectable CAC, 34% of patients with HIV had markedly increased IMT (≥1 mm) compared to no controls (p <0.0001). HIV-related factors were associated with IMT but not with CAC. In conclusion, patients with HIV and controls had similar rates of detectable CAC, while absolute CAC scores were modestly higher in the HIV group. Conversely, carotid IMT detected advanced subclinical atherosclerosis in patients with HIV even in the absence of CAC. Thus, with HIV, IMT is associated with disease-related factors and may be a more sensitive indicator of subclinical atherosclerosis than CAC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Secretory phospholipase A(2) (sPLA(2)) enzymes, produced and secreted in human blood vessels and hepatocytes, contribute to the development of atherosclerosis through mechanisms that are both dependent and independent of lipoprotein. We examined the effects of an sPLA(2) inhibitor on enzyme concentration and on plasma lipoproteins and inflammatory biomarkers in patients with coronary heart disease. METHODS: Patients aged 18 years and older with stable coronary heart disease from the USA and Ukraine were eligible for enrolment in this phase II, randomised, double-blind, placebo-controlled, parallel-arm, dose-response study. 393 patients were randomly assigned by computer-generated sequence to receive either placebo (n=79) or one of four doses of an sPLA(2) inhibitor, A-002 (1-H-indole-3-glyoxamide; 50 mg [n=79], 100 mg [n=80], 250 mg [n=78], or 500 mg [n=77] twice daily), for 8 weeks. The primary endpoint was the change in sPLA(2) group IIA (sPLA(2)-IIA) concentration or activity from baseline to week 8. Analysis was by modified intention to treat (ITT). The ITT population consisted of all patients who received one dose of study treatment; data for patients who dropped out before the end of the study were carried forward from last observation. This trial is registered with ClinicalTrials.gov, number NCT00455546. FINDINGS: All randomised patients received at least one dose and were included in the ITT population. Data for 45 patients were carried forward from last observation (36 in the A-002 group and nine in the placebo group); the main reason for dropout before completion was because of adverse events. 348 patients reached the primary endpoint (A-002 n=278, placebo n=70). Mean sPLA(2)-IIA concentration fell by 86.7%, from 15.7 pmol/L to 2.1 pmol/L, in the overall active treatment group, and by 4.8%, from 15.7 pmol/L to 14.3 pmol/L, in the placebo group (p<0.0001 treatment vs placebo). The reductions in sPLA(2)-IIA concentration in the A-002 groups were dose dependent (ranging from 69.2% in the 50 mg group to 95.8% in the 500 mg group) and differed significantly from placebo (p<0.0001 for all doses). In the 500 mg A-002 treatment group, there was one serious adverse event (exacerbation of underlying chronic obstructive pulmonary disease), but the proportion of patients reporting treatment-emergent adverse events did not differ from placebo. The main side-effects of the drug included headache (n=20), nausea (n=17), and diarrhoea (n=12). INTERPRETATION: The reductions in sPLA(2)-IIA concentration suggest that A-002 might be an effective anti-atherosclerotic agent. [ABSTRACT FROM AUTHOR]

Background: Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib.Methods: We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina.Results: At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change.Conclusions: Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects. Methods: We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. Results: The primary efficacy variable analyzing the progression of atherosclerosis--the change in percent atheroma volume--was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53). Conclusions: For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.). [ABSTRACT FROM AUTHOR]

We performed a cohort study of 392 postmenopausal women who had coronary disease to assess whether baseline serum endothelin-1 level predicts angiographic disease progression, nonfatal myocardial infarction, or death. Angiographic progression was defined as the annualized change in minimal lumen diameter of all qualifying lesions for each patient. Twenty-nine patients died or had a myocardial infarction during follow-up. Each picogram per milliliter increase in endothelin-1 was associated with a 1.8-fold increased risk of death or myocardial infarction. After adjustment for potential confounders, endothelin-1 remained a predictor of clinical events but was not correlated with angiographic progression. [ABSTRACT FROM AUTHOR]

Although the combined assessment of perfusion and function using rest electrocardiographic (ECG)-gated technetium-99m (Tc-99m) sestamibi single-photon emission computed tomographic (SPECT) imaging has been shown to improve sensitivity and accuracy over perfusion alone in the prediction of myocardial viability, no data are available comparing this technique with rest-redistribution thallium-201. Thirty patients with coronary artery disease and left ventricular dysfunction (ejection fraction < or = 40%) underwent rest-redistribution thallium-201 and rest ECG-gated Tc-99m sestamibi SPECT imaging before revascularization and rest ECG-gated Tc-99m sestamibi SPECT imaging at 1 or 6 weeks after revascularization. All thallium-201 and Tc-99m sestamibi images were interpreted by a consensus agreement of 3 experienced readers without knowledge of patient identity or time of imaging with Tc-99m sestamibi (before or after revascularization) using a 17-segment model. Concordance between techniques for the prediction of viability was 89% (kappa 0.556 +/- 0.109). With rest-redistribution thallium-201, sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy were 95%, 59%, 88%, 78%, and 86%, respectively. With rest ECG-gated Tc-99m sestamibi SPECT imaging, sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy were 96%, 55%, 87%, 80%, and 86%, respectively (p = NS vs rest-redistribution thallium-201). Although both techniques are comparable for detecting viable myocardium, rest ECG-gated Tc-99m sestamibi SPECT imaging allows direct assessment of both myocardial perfusion and ventricular function, which may be clinically useful in patients who require assessment of myocardial viability. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether exercise technetium-99m sestamibi gated single-photon emission computed tomography (SPECT) accurately distinguishes between patients with ischemic cardiomyopathy and patients with nonischemic left ventricular systolic dysfunction. Noninvasive tests have previously failed to accurately separate patients with ischemic cardiomyopathy from those with nonischemic cardiomyopathy. Technetium-99m gated SPECT imaging offers advantages that have the potential to overcome the limitations of previous studies. Thirty-seven adults with a left ventricular ejection fraction < or = 35%, including 24 patients with nonischemic cardiomyopathy and 13 patients with ischemic cardiomyopathy, were prospectively evaluated using symptom-limited metabolic exercise treadmill testing with technetium-99m sestamibi gated SPECT imaging. Interpretation of myocardial perfusion and regional wall motion was performed, using a 17-segment model. Summed stress, rest, and reversibility perfusion defect scores were determined, and the variance of segmental wall motion scores was computed. Summed stress, rest, and reversibility perfusion defect scores were significantly lower in nonischemic cardiomyopathy patients, compared with those with ischemic cardiomyopathy (summed stress defect score: 6.9 +/- 3.8 vs 32.9 +/- 7.7, respectively, p <0.001). Variability in segmental wall motion was also significantly lower in patients with nonischemic cardiomyopathy compared with those with ischemic cardiomyopathy (variance: 0.3 +/- 0.3 vs 1.2 +/- 0.8, respectively, p <0.001). Thus, assessment of myocardial perfusion and regional ventricular function with exercise technetium-99m sestamibi gated SPECT imaging can reliably distinguish between patients with ischemic cardiomyopathy and patients with nonischemic dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Objective: The cardiovascular benefits of low-dose colchicine have been demonstrated in patients with coronary disease. Its effects were evaluated in this prespecified analysis in patients with type 2 diabetes (T2D) from the Colchicine Cardiovascular Outcomes Trial (COLCOT)., Research Design and Methods: COLCOT was a randomized, double-blinded trial of colchicine, 0.5 mg daily, versus placebo initiated within 30 days after a myocardial infarction., Results: There were 959 patients with T2D enrolled and monitored for a median of 22.6 months. A primary end point event occurred in 8.7% of patients in the colchicine group and in 13.1% in the placebo group (hazard ratio 0.65; 95% CI 0.44-0.96; P = 0.03). Nausea was reported in 2.7% and 0.8% in the study groups (P = 0.03), and pneumonia occurred in 2.4% and 0.4% (P = 0.008)., Conclusions: Among patients with T2D and a recent myocardial infarction, colchicine, 0.5 mg daily, leads to a large reduction of cardiovascular events. These results support the conduct of the COLCOT-T2D trial in primary prevention., (© 2024 by the American Diabetes Association.)

Aims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis., Methods and Results: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98)., Conclusion: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype., Clinical Trial Registration: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939., Competing Interests: Conflict of interest: J.C.T. has received research grant and honoraria from Amarin; research grant from AstraZeneca; research grant, honoraria, and minor equity interest from DalCor; research grant from Esperion; research grant from Ionis; research grant and honoraria from Sanofi; research grant and honoraria from Servier; a patent on pharmacogenomics-guided CETP inhibition was obtained, and J.C.T. and M.P.D. are mentioned as authors. M.P.D. has a minor equity interest in DalCor and has received honoraria from DalCor. M.A.P. receives research support from Novartis; he serves as a consultant for AstraZeneca, Corvidia, DalCor, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Novo Nordisk, Roche, Sanofi, Servier, and Takeda; and has equity in DalCor. D.D.W. has received remuneration for participation in clinical trial committees from CSL Ltd, Daiichi Sankyo, DalCor, the Medicines Company, Novo Nordisk, Regeneron, Resverlogix, and Sanofi, and honoraria for lectures from DalCor and Pfizer. W.K. reports personal fees (consulting) from DalCor and consulting fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, Kowa, a Corvidia, Esperion, Genentech, Omeicos, Novo Nordisk, Daiichi Sankyo, and Amgen; personal fees (honorarium for lectures) from AstraZeneca, Novartis, Amgen, Sanofi, Bristol-Myers-Squibb, and Berlin-Chemie; grants and non-financial support (provision of reagents for biomarker measurements free of charge) from Roche Diagnostics, Beckmann, Singulex, and Abbott, outside the submitted work. A.P.M. has received personal fees for participation in study committee from DalCor, and personal fees for participation in study committees from AstraZeneca, Bayer, Novartis, and Fresenius. J.J.V.M. reports grants paid to his institution and fees as steering committee member from DalCor Pharma UK for the Dal-GenE study, during the conduct of the study; grants paid to his institution and fees as steering committee member from Oxford University and Bayer; grants paid to his institution from Theracos; grants paid to his institution and fees as steering committee from Abbvie; grants paid to his institution from Pfizer, Merck AstraZeneca, GlaxoSmithKline, and Novartis. J.W.J. and his department have received research grants from and/or was speaker (with or without lecture fees) in CME-accredited meetings sponsored by Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, The Medicine Company, The Netherlands Heart Foundation, CardioVascular Research The Netherlands (CVON), The Netherlands Heart Institute and the European Community Framework KP7 Programme. H.D.W. reports grants paid to his institution and fees as steering committee member from DalCor Pharma UK for the Dal-GenE study, during the conduct of the study; grants paid to his institution and fees as steering committee member from Sanofi-Aventis, Regeneron Pharmaceutics, National Institutes of Health (USA), CSL Behring, American Regent, Sanofi-Aventis Australia Pty Ltd, and Esperion Therapeutics Inc, outside the submitted work. F.L.T., T.H., and D.M.B. are employed by and have minor equity interest in DalCor. Other authors report no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)