Any thought on why the Lovaza study you cited would show harm and this EPA study showed dramatic benefit? What was different between the two otherwise similar studies? --AVII
I do have some thoughts on that. Glad you asked ;)
Basically I think the trend for harm in the n-3 study was mostly standard deviation seen between two well-stratified groups given different ineffective treatments (4g/d corn oil vs 4g/d n-3). Ineffective because high-dose n-3 may counteract concurrent benefits, and optimal dose statin and low dose aspirin regimens may mask the potential for n-3 to show additional benefit. If the window of time in which intervention was sought was smaller, however, it may have helped somewhat. Imo..
Subjects in the EPA study were on low dose pitavastatin. This would leave some residual benefit "on the table" that could be had with higher dose statin intervention. They also received EPA intervention within 24 hrs of PCI. That's an important consideration as well (as I'll show below). In the n-3 study it was 4-8 days after a MI that they received n-3 (and about half probably did not get a PCI--many received thrombolysis). And the subjects in the n-3 study were likely on high dose statins.
There is also a genetic consideration, in that 100% of those in the EPA study were Japanese. Elsewhere I've submitted data that show Japanese may be able to better utilize EPA (and DHA) on a cellular level (not just spiked blood serum levels).
There are pretty dramatic differences between high and low dose pitavastatin treated subjects wrt various markers:
Two groups received once-daily pitavastatin 2 mg or atorvastatin 10 mg and two groups received the same treatment for 4 weeks followed by forced titration to pitavastatin 4 mg or atorvastatin 20 mg. After 12 weeks, pitavastatin produced a noninferior reduction from baseline in LDL-C and total cholesterol (TC) concentrations compared with atorvastatin (Figure 1). The mean reduction in LDL-C was 37.9% and 37.8% for pitavastatin 2 mg and atorvastatin 10 mg respectively and 44.6% and 43.5% for pitavastatin 4 mg and atorvastatin 20 mg respectively. Pitavastatin and atorvastatin were not significantly different in terms of changes in nonHDL-C, TG, apoB or apoA1. Most patients reached NCEP LDL-C targets (pitavastatin 4 mg, 77.9%; atorvastatin 20 mg, 70.6%; pitavastatin 2 mg, 56.8%; atorvastatin 10 mg, 65.7%) and European Atherosclerosis Society (EAS) LDL-C targets (pitavastatin 4 mg, 78.5%; atorvastatin 20 mg, 76.5%; pitavastatin 2 mg, 56.8%; atorvastatin 10 mg, 59.8%), with no significant difference between treatment groups. HDL-C levels increased from baseline by 4% and 5% with pitavastatin 2 mg and 4 mg respectively compared with 3% and 2.5% with atorvastatin 10 mg and 20 mg respectively.
Plaque regression and stabilization are also dose dependent:
Among the reports with IVUS, Taguchi et al. reported that early statin therapy reduced the necrotic core component in patients with ACS, even in the case of plaque progression (37). A study with rosuvastatin (low dose: 5 mg/day, high dose: 40 mg/day) in patients with ST-segment elevation myocardial infarction (STEMI) clarified that the necrotic core component was reduced only in the high-dose rosuvastatin group (low dose; baseline 44.6±38.2 mm3, 12-month follow-up 41.2±40.3 mm3, P<0.29 vs. high dose; baseline 47.4±38.2 mm3, 12-month follow-up 40.7±34.4 mm3, P=0.003).
It's all about residual risk, residual benefit, and I think for ACS patients immediately following PCI, high dose statins fit the bill. But there's a clear difference in effect when this is delayed:
Plaque fissuring or rupture was determined to be a trigger for coronary thrombosis, which is the cause of ACS in the majority of cases. Atherosclerotic plaque that is susceptible to disruption is identifiable by certain histological features: it usually contains a large lipid pool; an accumulation of macrophages; and a thin fibrous cap (4–7). The mediators contributing to plaque vulnerability may be divided into extrinsic and intrinsic factors (8,9). Extrinsic factors actually trigger plaque disruption and include circumferential stress, hemodynamic shear stress, vasospasm or a prothrombotic milieu (9–12). Intrinsic factors are responsible for susceptibility to plaque rupture or directly cause it. Intrinsic factors include the size and composition of the lipid core, neovascularization, endothelial erosion/fissure, low cap thickness, inflammation, increased levels of matrix degradation enzymes, a decreased number of smooth muscle cells (SMCs) and low collagen content, outward remodelling and nodular calcification (9).
In the Orofiban in Patients with Unstable Coronary Syndromes/Thrombolysis in Myocardial Infarction (OPUS/TIMI 16) study (129), mortality at one month was reduced in patients treated with lipid-lowering drugs (RR 0.30; P<0.001). The analysis of the Sibrafiban Versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) trial demonstrated lower mortality in statin-treated patients at three months (RR 0.58; P<0.05) (130).
It should, however, be emphasized that the risk reduction in most of the above mentioned analyses was far greater than anything observed in large randomized controlled trials; it is, therefore, very likely that there were unaccounted confounders influencing the results...
The Pravastatin in Acute Coronary Treatment (PACT) trial (135) evaluated the effect of pravastatin administration within 24 h of the onset of symptoms in patients with ACS. The recruitment of 10,000 patients was planned; however, the study was stopped early. A total of 3408 patients were randomly assigned to pravastatin 20 mg, 40 mg or placebo. After 30 days of follow-up, no significant difference in the occurrence of major adverse cardiac events (MACE) was observed.
In the Prevention of Ischemic Events by Early Treatment of Cerivastatin Study (PRINCESS) (136), patients were randomly assigned within 48 h of admission for ACS to cerivastatin or placebo. This trial was prematurely stopped after cerivastatin was withdrawn from the worldwide market. Data obtained from a total of 3600 patients who were followed-up for 4.5 months were analyzed; no significant difference in the occurrence of MACE was found between the groups.
The Lipid-Coronary Artery Disease (L-CAD) trial (140) was primarily designed to examine the effect of pravastatin on angiographic regression of atherosclerosis. In the L-CAD study, 126 patients who had undergone PCI for ACS were randomly assigned to pravastatin 20 mg to 40 mg (with or without cholestyramine and/or nicotinic acid) or to usual care determined by a family physician, and patients were enrolled by hospital discharge. After two years of follow-up, fewer patients in the pravastatin group experienced MACE compared with the usual care group (OR 0.28; P=0.005); it should, however, be mentioned that the event reduction in this small open-label study is far greater than in large, placebo-controlled trials, again indicating possible unaccounted confounders that influenced the results.
Recently, several meta-analyses of randomized clinical trials evaluating statin therapy started early after ACS onset have been published. They have clearly shown that administration of statins does not influence the rates of nonfatal myocardial infarction, the number of cerebrovascular events or mortality rate within the first four months. Thereafter, however, the beneficial effect of statin therapy on cardiovascular events became detectable, reaching statistical significance at six months and persisting for two years of follow-up (HR 0.84 [95% CI 0.76 to 0.94]) (143–146).
It can be concluded that these prospective trials have shown safety and, in some cases, also benefit of the early initiation of statin therapy after ACS. It is important to emphasize that atorvastatin 80 mg is the only agent/dose proven in randomized controlled trials to have benefit after ACS, either against placebo (MIRACL) or against another statin regimen (PROVE-IT). Despite this evidence, now available for more than 10 years, it is surprising that only about one-half of patients with ACS are treated with an intensive statin regimen, according to a recent analysis (147). Thus, there remains a gap between evidence and clinical practice in the use of statins after ACS .
It is necessary to stress that all of the above-mentioned trials were designed for early (in some cases ‘very early’) secondary prevention, but not for initial, emergency department therapy of ACS. In all these studies, patients were randomly assigned at least several hours and, in most cases, even several days after hospital admission. During such a long period of time, the majority of patients were already clinically stable (clinical stabilization was also an inclusion criterion in some of the trials). In the context of the above-described pathogenesis of vulnerable plaque development and mechanisms of the pleiotropic effects of statins, it is obvious that there are relevant reasons to test administration of these drugs not only for secondary prevention, but also directly for the treatment of ACS when administered to patients who are particularly unstable.
As discussed above, the pleiotropic effects of statins may affect different pathogenic pathways participating in the development of vulnerable plaque and in the pathogenesis of ACS. Expanding this suggestion, statins may significantly contribute to plaque stabilization, reduction of thrombus formation and acceleration of fibrinolysis. It may, therefore, be fruitful to investigate possible additional favourable effects of immediate, first-line statin therapy in the emergency department or catheterization laboratory at the time of coronary instability, rather than initiation after the acute event or at hospital discharge
For many years, ACS was recognized as a strong stress factor associated with marked spontaneous changes in lipid parameters, and it has been speculated that the effect of statins on cholesterol levels can be detected only after several weeks of therapy. Recently, however, it has been shown that the current management of ACS results in only clinically insignificant spontaneous changes in lipoprotein levels during the course of ACS (162). In general, 90% of the eventual LDL reduction with statins is seen 14 days after initiation of treatment; however, smaller effects may be observed much sooner.
These results indicate that statin therapy initiated early in ACS patients can influence lipid parameters as quickly as inflammatory markers. It is possible that rapid reduction of cholesterol levels may help to promote early coronary plaque stabilization by statins.
The first multicentre, randomized, double-blind, placebo-controlled study that focused on the effect of statin therapy initiated as first-line therapy of ACS was the Fluvastatin in the therapy of Acute Coronary Syndrome (FACS) trial (166). One-hundred fifty-six ACS patients were randomly assigned at the time of hospital admission to fluvastatin 80 mg or placebo. Study medication was administered for 30 days, after which time patients in both groups were encouraged to continue with open-label statin therapy. The primary end points were CRP, IL-6 and pregnancy-associated plasma protein A (PAPP-A) levels, which remained the same in both groups. In contrast, fluvastatin therapy was associated with a significant reduction in the cardiovascular event rate at one year (combined secondary end point) (11.5% versus 24.4%; OR 0.40 [95% CI 0.17 to 0.95]; P=0.038). Despite the small study population and other limitations, results of the FACS trial indicate possible benefits from initiation of statin therapy as early as possible in ACS patients. A favourable effect of atorvastatin 80 mg administered as first-line treatment of ACS in patients with ST elevation was recently reported by Kim et al (167). In their STATIN STEMI trial, 171 patients were randomly assigned to atorvastatin 80 mg or atorvastatin 10 mg before primary PCI. The authors found improved coronary flow, faster ST segment resolution and a trend toward a lower cardiovascular event rate in the intensive atorvastatin group.
CONCLUSION
Statins were introduced to clinical practice as lipid-lowering drugs for the treatment of high blood cholesterol levels. They were shown to be highly effective in hypercholesterolemic patients for primary and secondary prevention of CAD. Their efficacy in secondary prevention was demonstrated in large prospective morbidity and mortality clinical trials involving patients with stable CAD; these studies enrolled patients at least several months after the onset of ACS. Later, it was observed that statins exert a favourable effect, not only in hypercholesterolemia, but also in patients with normal or low cholesterol levels and, therefore, nonlipid-mediated effects of statins have been suggested. The discovery of the pleiotropic effects of statins opened the possibility for new indications for statin treatment. Several randomized trials have demonstrated the safety and, in some cases, the efficacy of statin therapy if initiated early after the onset of ACS. Extension of knowledge regarding the pleiotropic effects of statins, together with the increasing understanding of the pathogenesis of ACS have, however, shifted the initiation of statin therapy closer to the onset of symptoms.
RESULTS: Peri-procedural MI (the primary endpoint) occurred in 7.5% of patients randomized to pre-PCI statin loading vs. 15.8% of controls (odds ratio [OR] 0.44, 95% CI 0.35-0.56, p<0.00001). Significant reductions in peri-procedural MI were observed in patients with stable angina (OR 0.33, p<0.00001) or NSTE-ACS (OR 0.32, p<0.0001) and in mixed populations (OR 0.66, p=0.02). Statin loading was also associated with a reduction in the combined endpoint of death, spontaneous MI and target vessel revascularization ((OR 0.59, 95% CI 0.38-0.92, p=0.02), but this benefit was observed only in the subgroup of patients undergoing PCI for NSTE-ACS (OR 0.18, p=0.0005).
CONCLUSIONS: These results are consistent with a significant short-term clinical benefit of pre-PCI statin loading in statin-naïve patients with NSTE-ACS followed by standard statin dosing after the procedure.
and
METHODS: These multinational authors, coordinated in Italy, performed a patient-level meta-analysis of 3,341 participants in 13 randomized controlled trials of high-dose statin pretreatment vs. low-dose or no statins (controls) prior to PCI (one was an ED-based study using 80mg of atorvastatin). There were no differences in periprocedural antithrombotic treatment, and all of the patients received post-procedure statins.
RESULTS: Rates of periprocedural MI were 6.8% in the intervention group receiving high-dose statin pretreatment vs. 11.9% in controls (odds ratio [OR] 0.54, p<0.00001), and corresponding rates of periprocedural myocardial injury, based on post-PCI troponin levels, were 34.9% vs. 47.7%, respectively (OR 0.59, p<0.00001), and 5.9% vs. 9.0% in the subgroup undergoing PCI for acute coronary syndrome (OR 0.64, p=0.06). Rates of major adverse cardiac events (defined as death, MI or target vessel revascularization) at 30 days were 7.4% in the intervention group vs. 12.6% in controls (OR 0.56, p<0.00001) when periprocedural MI was included as an outcome, and 0.6% vs. 1.4%, respectively (OR 0.44, p=0.05) when periprocedural MIs were excluded.
So, there was a residual benefit left out there from the dose being low. And the timing of introducing the EPA, especially in 100% Japanese subjects probably genetically superior at utilizing it, was optimal, being within 24 hrs of PCI. The dose was at 1.8 g/d, which may also be optimal. As the n-3 study reported, and other studies confirmed, a high dose of n-3 results in conflicting markers of pro and anti-inflammation. It's possible these could tend to cancel each other out.
I also think the out of balance strat wrt strokes is problematic, and the low number of events after 1 year of follow up, which may have balanced out more per group at 1.5 - 2 years.
On strokes, 15 had prior in control vs 8 in EPA group. Although 14 had prior MI in EPA group vs 7 in control, it seems that prior stroke is a much higher risk factor for future CV death than prior MI. And possibly higher rates of revascularization:
More than 480,000 patients underwent elective noncardiac surgery. A history of stroke was associated with an increased risk of major adverse cardiovascular events and death, particularly if time elapsed between stroke and surgery was less than 9 months, according to a study in the July 16 issue of JAMA.
Crude incidence rates of MACE among patients with (n?=?7137) and without (n?=?474?046) prior stroke were 54.4 (95% CI, 49.1-59.9) vs 4.1 (95% CI, 3.9-4.2) per 1000 patients.
Conclusions and Relevance A history of stroke was associated with adverse outcomes following surgery, in particular if time between stroke and surgery was less than 9 months.
That's over 13 times the risk of MACE in those with prior stroke vs non. Especially if stroke was within 9 months.
Here's another, more related study:
RESULTS:
A total of 2016 AF (atrial fib) patients (1104 women) were included in the final analysis. Multivariate Cox regression analysis showed that the risk factors for stroke were female gender (1.419 (1.003-2.008), p=0.048), age ≥ 75 (2.576 (1.111-4.268), p<0.001), previous stroke/TIA (2.039 (1.415-2.939), p<0.001), LVSD (1.700 (1.015-2.848), p=0.044) and previous major bleeding (2.481 (1.141-5.397), p=0.022).
For MACE, age ≥ 75 (3.042 (2.274-4.071), p<0.001), heart failure (1.371 (1.088-1.728), p=0.008), previous stroke/TIA (1.560 (1.244-1.957), p<0.001), LVSD (1.424 (1.089-1.862), p=0.010) and COPD (1.393 (1.080-1.798), p=0.011) were independent risk factors.
Another study found:
In-hospital mortality among patients with stroke was substantially higher than in patients without stroke after PCI for ACS. Rates of MACE, MI, renal failure requiring dialysis, intracranial bleeding, and major bleeding followed the same pattern (table 1).
etc.
There were also twice as many Killip class 3 subjects in control arm (10 vs 5), who are at the highest risk of MACE.
Angiographic study showed significantly lower final thrombolysis in myocardial infarction 3 flow in patients with Killip III compared with those with Killip II and I (83.5% vs. 94.9% vs. 95.7%, p<.0001). The incidence of multiple vessel disease was also notably higher in Killip III than in Killip II and I (65.7% vs. 13.9% vs. 53.8%, p<.001).
Besides, the incidence of advanced congestive heart failure (defined as greater than or equal to New York Heart Association functional class 3) during hospitalization was remarkably higher in Killip III compared to Killip II and I (71.3% vs. 13.9% vs. 6.6%, p<.001). Furthermore, the 30-day mortality and 1-yr cumulative mortality were notably higher in Killip III than in Killip II and I (20.0% vs. 4.2% vs. 1.7%, p<.001 and 31.7% vs. 7.9% vs. 4%, p<.001, respectively).
It seems where it mattered most (prior stroke and Killip class III) the two groups were imbalanced. Combined, that put 24 subjects with much higher risk of MACE in control vs 12 of the same risk in EPA group. And that matters a lot when we are talking a *total* of just 29 PE events split between groups over 1 yr follow-up (btw the Omacor study had 78 PE events over 1.5 yrs follow up).
The "58% RRR" you calculated is probably at least overblown.
The authors of the n-3 study noted:
It is also possible that the high doses of concentrated n-3 fatty acids applied in this study exceeded some optimal threshold level, outweighing the beneficial effect or even leading to an apparent adverse effect. We chose a daily dose of 4 g n-3 fatty acids, >10 times the dose given in DART and 4 times the dose given in the GISSI Prevention Study. A possible adverse effect of high doses of n-3 fatty acids on cardiac events was hypothesized in previous studies using high-dose ethylester compounds of EPA and DHA (39, 40) on the basis of observations of a reduction in vitamin E and an increase in thiobarbituric acid–reactive substances. A proinflammatory response induced by peroxidation may serve as a biological mechanism for an adverse effect. The nonsignificant increase of recurrent MIs in the n-3 group may be consistent with a dose-optimum hypothesis.
The strongest effect of fish intake was shown in the randomized open Diet and Reinfarction Trial (DART) (27), in which men instructed to eat fish after myocardial infarction (MI) had a 29% decline in all-cause mortality compared with men in the control group. That study was performed before the standard use of aspirin in patients with acute MI, a drug that may partly mask the beneficial effects of n-3 fatty acids...
Finally, competing interventions including aspirin may have masked the potential to demonstrate an effect of n-3 fatty acids in our study. DART (27) was carried out in the era before aspirin and thrombolytic agents, whereas >60% of patients in the Mediterranean study (31) were taking antiplatelet agents. Patients in the GISSI Prevention Study (28) were treated with the same pharmacologic background therapy as in this study, but a smaller proportion of patients in the GISSI Study were given statins during follow-up.
The lack of beneficial effect and a tendency toward an adverse effect may be related to a dose optimum below the chosen dose in this trial. It is also possible that corn oil exerted a protective effect of similar or greater strength than n-3 fatty acids or that competing interventions masked a potential difference between our treatment groups.
And I guess we could add time-to-intervention following acute MI may also be of significant importance.
Btw an interesting little aside on JELIS:
JELIS randomized 14,981 high-risk pri- mary prevention patients and 3,664 secondary prevention patients to EPA or usual care in a prospective open-label, blinded end-point trial and followed them for 4.6 years. All patients continued on their usual diets, averaging about 900 mg/d of EPA and DHA [13].
...differences in serum EPA levels suggest that tissue EPA and DHA are markedly higher in Japan than in the West.
So to put this altogether, I think the positive results from the ACS study with 1.8g/d EPA in an all-Japanese cohort may be due to:
-probable confounding, at least to some degree, by the imbalance of prior stroke and Killip class III subjects in control vs EPA group (and maybe other imbalances not accounted for from this small sample).
-low dose statin (not SOC for non-Japanese with ACS) being given to all subjects, leaving residual benefit behind, that was possibly procured by 1.8 g/d EPA dosing (anti-inflammatory, additional plaque stability, etc.)
-timing of intervention within 24 hours of PCI, which is crucial to prevent MACE in these subjects. This could potentially be n-3 or any anti-thrombotic agent, if there is residual benefit not being met by high dose statins.
-the optimal dose of EPA (or EPA/DHA) may be 1.8g/d, and not 4g/d (which lowers HDL-C and serum vit E, and increases TBARS--none of which occurs at 2g/d)
-100% Japanese cohort, who are genetically superior at utilizing EPA and DHA, and who are already getting higher levels of DHA in their diet, which may counteract some of the negative effects of EPA-only dosing (such as decreased HDL).
In the n-3 study, all subjects received Omacor 4-8 days after MI (not an optimal window), and were given 4g/d. The amount of DHA was higher than EPA, at a ratio of 2:1. There was essentially no difference between groups in MACE. The HR was insignificant at any rate, though a trend in favor of placebo group did surface. I suppose AMRN longs would like to assume that is due to the DHA, but again, I would caution against such convenient conclusions :) There is no evidence dosing with DHA, especially when taken along with EPA, and the very small increase in LDL-C that results (while LDL particle size increases and LDL-P concentration decreases), increases risk of MACE. Though EPA at 4g/d alone, and in subjects who are not getting much DHA at all, could be harmful. And 4g/d of any PUFA can be harmful (as well as beneficial).
The differences between the EPA study in ACS patients and R-IT are numerous and as follows:
-R-IT subjects are on optimal/high dose statins. Those with ACS are certainly on high dose statins -R-IT subjects are non-Japanese westerners -most R-IT subjects do not have ACS -R-IT subjects do not have diets high in DHA, which may help counterbalance some of the negative effects of 4g/d EPA -R-IT subjects are receiving 4g/d EPA, not 1.8g/d EPA. This may exceed an optimal dose threshold, and cause more harm than benefit, especially with regard to its negative impact on HDL-C, HDL2, oxLDL uptake by macrophages, TBARS, serum vit E, and fasting glucose levels.
That's all I've got!
Cheers
*nothing more public from me on AMRN until the article I will post on SA.
GL guys
"Think for yourselves and let others enjoy the privilege to do so, too."
