Oxygen Model of Heart Disease – More Evidence

              Oxygen Model of Heart Disease

More Evidence

Majid Ali, M.D

A core tenet of my Oxygen Model of Heart Disease is that heart attacks are, first and foremost, problems of the circulating blood, not of coronary artery walls. This model also predicts that heart health program directed at coronary arteries will have limited, if any, benefits if they do not effectively address the matters of the health of the circulating blood.

Specifically, in the context of coronary artery plaques being the primary cause of coronary heart attacks, the model predicts that drugs that inhibit inflammation in the coronary plaques will not prevent heart attacks. A clear statement that this prediction proved right was published by New England Journal of Medicine on May 1, 2014. Consider the following quote from the Journal article on thi date:

“Conclusions – In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke.” New England Journal of Medicine. May 1, 2014, (2014; 370:1702-1711).

Another consideration is that 96% of the patients at trial closeout were taking statins, which have been shown to reduce levels of lipoprotein-associated phospholipase A2 by up to 35%.19-21 In addition, in the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, among patients with stable chronic coronary heart disease, more than half the treatment effect of pravastatin in reducing rates of death from coronary heart disease or myocardial infarction was estimated to be due to an association with a reduction in levels of lipoprotein-associated phospholipase A2.22 Incremental benefits of inhibiting lipoprotein-associated phospholipase A2 activity, if present, could be less in patients treated with statins.

May 1, 2014

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x Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease

The STABILITY Investigators. N Engl J Med 2014; 370:1702-1711May 1, 2014

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AbstractArticleReferencesCiting Articles (1) Background

Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.

Full Text of Background…

Methods

In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).

Full Text of Methods…

Results

During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).

Full Text of Results…

Conclusions

In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.)

Discussion

In this large, multicenter, randomized trial involving patients with stable chronic coronary heart disease who were followed for a median of 3.7 years, darapladib did not significantly reduce the incidence of the primary end point of cardiovascular death, myocardial infarction, or stroke. There were no significant reductions in the incidence of the components of the primary end point, as assessed individually, or in the rate of all-cause mortality. There was a nominally significant reduction in the secondary end points of major and total coronary events, which is a signal of possible efficacy. The lack of effect of the administered dose of darapladib on the primary end point may relate to a smaller effect on vulnerable coronary plaque than was anticipated on the basis of previous studies.12,13

It is possible that the coronary risk among patients in our study may already have been minimized by concurrent therapy. The trial was designed to test the incremental effect of a new treatment administered in patients who were receiving a high level of standard of care for secondary prevention at baseline. Thus, more than a third of the patients had an LDL cholesterol level of less than 70 mg per deciliter (1.81 mmol per liter) at baseline, and revascularization had been performed in 75% of the patients before randomization. High rates of the use of evidence-based medications were maintained throughout the trial. These standards of care are consistently higher than those that were observed in patients with stable chronic coronary heart disease who were included in previous large international registries.16-18 These factors probably reduced event rates in the two study groups and may have reduced the proportion of events that were modifiable.

Another consideration is that 96% of the patients at trial closeout were taking statins, which have been shown to reduce levels of lipoprotein-associated phospholipase A2 by up to 35%.19-21 In addition, in the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, among patients with stable chronic coronary heart disease, more than half the treatment effect of pravastatin in reducing rates of death from coronary heart disease or myocardial infarction was estimated to be due to an association with a reduction in levels of lipoprotein-associated phospholipase A2.22 Incremental benefits of inhibiting lipoprotein-associated phospholipase A2 activity, if present, could be less in patients treated with statins.

There was a nominally significant reduction of approximately 10% in the rate of the prespecified secondary composite end points of major and total coronary events. The effects on these end points were consistent across the components of these composite end points, including death from coronary heart disease, myocardial infarction, coronary revascularization, and hospitalization for unstable angina, and it is possible that the inhibition of lipoprotein-associated phospholipase A2 may reduce these measures of coronary disease risk. However, these findings should be considered exploratory and of uncertain importance in light of the lack of effect on the primary end point.

In accordance with previous findings, there was an increase in the rate of diarrhea among patients receiving darapladib, as compared with those receiving placebo, along with increases in the rates of odor (in skin, feces, and urine), an effect that is thought to be related to the sulfhydryl group in the darapladib molecule. Because of the occurrence of these events, there were more study-drug discontinuations in the darapladib group than in the placebo group, with most discontinuations occurring during the first year. The mechanisms and clinical significance of the changes in renal laboratory measures and of the renal serious adverse events are uncertain.

In conclusion, we evaluated a novel mechanism for reducing plaque vulnerability by inhibition of lipoprotein-associated phospholipase A2 with darapladib in patients with stable coronary heart disease who were receiving guideline-based background medical therapy. Darapladib did not significantly reduce the rate of the primary end point of cardiovascular death, myocardial infarction, or stroke.

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