VESL Wall, Issue #5, July 2021
Issue #5, July 2021

This month on the VESL Wall, we highlight recently published data on days alive out of hospital following intervention for moderate to severe myocardial ischemia, the persistent effect of a primary prevention strategy with statins in patients with risk factors for ASCVD, and the Lp(a) and LDL proteome using mass spectrometry. See all issues of the VESL Wall at

Dr. Liam Brunham walks us through the VESL Wall Issue #5 in this 11-minute video >> Video Summary VESL Wall Issue #5
A prespecified patient-focused outcome analysis of the ISCHEMIA trial

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) study compared outcomes following invasive and conservative management strategies for patients with moderate to severe myocardial ischemia. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. In the original trial, there was no statistically significant difference in the primary endpoint in patients treated with an initial invasive strategy, as compared with an initial conservative strategy, over 3.2 years. In this prespecified analysis, the authors evaluated a more patientoriented outcome, days alive out of hospital (DAOH), following the two treatment approaches.

When the days spent in hospital due to the protocol-defined invasive interventions were included, there was a statistical difference favoring the conservative management arm at one month, one year, and two years post-randomization. The statistical difference disappeared at the three- and four-year time points. It should be noted the actual differences were small, between 2.4 and 6.3 mean days over the course of the study. If the initial hospitalizations due to protocol-defined procedures are omitted, the differences are not statistically significant at any timepoint. When these initial hospital stays are excluded, the mean number of stays per patient was lower in the invasive management group (mean [SD], 0.6 [1.4] vs 0.7 [1.4]; P = 0.001). Cardiovascular stays were lower in the invasive management group (685 of 4002 [17.1%] vs 1095 of 1897 [57.8%]; P < .001), including fewer stays for spontaneous MIs and for unstable angina. Non-cardiovascular stays were similar in both groups. The data can provide a patient-focused metric for shared decision-making in the management of stable CAD.

Read more: [Sosido link] White HD, O'Brien SM, Alexander KP, et al. Comparison of Days Alive Out of Hospital With Initial Invasive vs Conservative Management: A Prespecified Analysis of the ISCHEMIA Trial [published online ahead of print, 2021 May 3]. JAMA Cardiol. 2021;e211651. doi:10.1001/jamacardio.2021.1651

Evaluating the persistence of primary prevention strategies beyond the active treatment phase

The HOPE-3 study evaluated the effects of primary prevention with a statin and/or blood pressure (BP) lowering medication using a 2x2 factorial design in intermediate risk patients without cardiovascular disease. Participants were invited to continue in a passive follow-up study after the completion of the active study phase, to evaluate if the effects persisted. Seventy-eight percent of subjects opted into the follow-up study, with participants balanced with respect to the original study arms. Medication use in the follow-up phase was at the discretion of the usual care physician, and in the first year of observation, 36% of rosuvastatin patients and 38% of placebo patients had been prescribed a statin.

During the follow-up phase, patients originally randomized to rosuvastatin had a further 20% reduction in risk of composite MI, stroke, or CV death (HR 0.80, 95% CI 0.64–0.99) and a trend to lowered rates of composite MI, stroke, CV death, resuscitated cardiac arrest, heart failure and coronary revascularization (HR 0.83, 95% CI 0.68–1.01). A 46% reduction in coronary ischemic events was also observed (HR 0.54, 95% CI 0.34–0.86). There was a 21% benefit over the full 8.7 years since randomization for composite MI, stroke, or CV death (HR 0.79, 95% CI 0.69–0.90). The data suggest a legacy effect and that the benefits of primary prevention may be underestimated if patients are not followed beyond the active treatment phase.

Read more: [Sosido link] Bosch J, Lonn EM, Jung H, et al. Lowering cholesterol, blood pressure, or both to prevent cardiovascular events: results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants [published online ahead of print, 2021 May 8]. Eur Heart J. 2021;ehab225. doi:10.1093/eurheartj/ehab225

Comparative analysis of the Lp(a) and LDL proteomes

Bourgeois and colleagues used mass spectrometry to compare the proteomic profiles of Lp(a) and LDL in 8 male and 7 female healthy subjects. After discovery and replication phases, they found fifteen proteins that were preferentially associated with Lp(a) particles compared to LDL. No proteins were preferentially associated with LDL compared to Lp(a), suggesting that the Lp(a) proteome is richer than that of LDL. These 15 proteins are involved in negative regulation of peptidase activity, regulation of insulin growth factor, transport by insulin growth factor, extracellular structure organization, protein processing, and regulation of binding. Further analysis suggested that the proteins may contribute to a shared function. The Lp(a) proteome also included several proteins associated with poor cardiovascular outcomes.

A human protein atlas derived from the INTERVAL blood donation study was used to analyze the plasma proteosome of patients with lifelong elevated Lp(a) and LDL. After correcting for multiple testing, 18 possible plasma proteins were identified that may be influenced by elevated LDL, while none appeared to be influenced by elevated Lp(a).

Read more: [Sosido link] Bourgeois R, Girard A, Perrot N, et al. A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization. CJC Open. 2020;3(4):450-459. Published 2020 Dec 3.


Compared to invasive approaches, moderate to severe myocardial ischemia patients managed with a conservative strategy experienced more days alive out of hospital for timepoints up to 2 years in the ISCHEMIA study. This difference became non-significant in years 3 and 4. Patients who received rosuvastatin as primary prevention for ASCVD continued to benefit even after the active treatment phase compared to those who were initially randomized to placebo. Proteomic profiling of Lp(a) and LDL suggests a more diverse proteome for Lp(a), with several proteins associated with poor CV outcomes forming part of the Lp(a) proteome.

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