william bowden, do, facc january 22, 2020 · amount of fish and/or omega-3 (tavazzi et al. lancet,...

William Bowden, DO, FACC

January 22, 2020

Dietary SupplementsPhysicians tend to regard Dietary Supplements as having little or no true medical benefit and tend to acquiesce to our patients (“it probably won’t help but it can’t hurt”).

Both statements are incorrect – there is an extensive amount of preclinical and clinical data on their impact and CV outcomes.

Dietary Supplements

Prescription drugs: well-controlled clinical trial assessing efficacy and safety

OTC: often former prescription drugs but include dietary supplements

1994 Dietary Supplement Health and Education ACT (DSHEA): must include “dietary supplement” on labels and cannot make claims about potential therapeutic or preventative effects

In 2018: Exceeded $30 billion in US, $115 billion worldwide

Dietary Supplements and the Heart

• Omega-3 Fatty Acids

• Vitamin Supplements

• Coenzyme Q10

• Red Yeast Rice

• Inorganic Nitrate Supplements

• Vitamin D and Calcium

Omega-3 Fatty Acids❖Trials dating back to 2002 were generally accepted as

having no CVD benefits

❖Three recent major trials did show benefits:

Vitamin D and Omega-3 Trial (VITAL Trial) [1]

A Study of CV Events in Diabetes (ASCEND Trial) [2]

Reduction of CV Events with Icosapent Ethyl Intervention Trial (REDUCE-IT Trial) [3]

[1] Manson et al.; NEJM 2019 Jan 3, 380(1): 23-32[2] Bowman et al.; NEJM 2018 Oct 18:379(16):1540-1550[3] Bhatt et al.; NEJM 2019 Jan 3; 380(1):11-22

Omega-3 Fatty Acids: VITAL Trial Over 25,000 Pts were assigned to one of three groups:

1 gm/d omega-3 acid ethyl esters [O3AEE; providing 840mg EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid)]

2,000 IU of Vit D3 (generic cholecalciferol)

Both O3AEE and Vit D3

Dual placebo

Followed for approximately 5 years: Could the risk for cancer, heart disease and stroke be reduced in patients who did not have a prior history of these illnesses?

Omega-3 Fatty Acids: VITAL Trial➢O3AEE demonstrated no benefit for cancer outcomes

over placebo

➢O3AEE did not significantly reduce major CV events (the trial’s primary outcome)

➢Conclusion: “supplementation with n-3 fatty acids did not result in a lower incidence of major CV events or cancer” over placebo – widely reported in the press

Omega-3 Fatty Acids: VITAL TrialStatistically significant prespecified secondary outcomes:

28% reduced risk for MI

50% reduced risk for fatal MI

17% reduced risk for total coronary heart disease events (1)

These effects were most pronounced in Pts with low fish intake (below the median of 1.5 servings per week) and African Americans

Omega-3 Fatty Acids: VITAL Trial❖Pts with low fish intake who were in the O3AEE group

had a significant 19% reduction in the primary end point but not Pts with higher fish intake.

❖African Americans in the O3AEE group:

• 77% reduction in MI

• 49% reduction in coronary revascularization

• 53% reduction in total coronary heart disease

Omega-3 Fatty Acids: VITAL Trial➢VITAL was considered a “null” study: the primary end point

of composite major CV events was not significantly reduced (8% reduction, 95% CI, -20% to 6%)

➢Primary end point was unaffected because it was a combination of 3 CV outcomes, 2 that were not reduced by O3AEE (total stroke and death from CVD)

➢Should be a positive trial especially given the low doses of EPA and DHA (< 1 gm/day) and short follow up (5yrs)

Omega-3 Fatty Acids: ASCEND Trial 15,480 Pts with diabetes and no Dx of CVD

Same omega-3 product and dose (840 mg of EPA + DHA) versus placebo (1gm capsule of olive oil)

Considered a null trial: the primary end point of nonfatal MI, nonfatal stroke, TIAs and vascular death (fatal CVD, fatal stroke and other vascular deaths) was only 3% lower (not statistically significance) in omega-3 group

Omega-3 Fatty Acids: ASCEND Trial

CVD death was significantly reduced by 19%

▪ Total CVD deaths should not be dismissed simply because the low dose of omega-3 fatty acids did not reduce the risk for all possible CVD end points

Omega-3 Fatty Acids: REDUCE-IT Trial Icosapent ethyl (IPE) or Vascepa (Amarin Corp)

Second FDA-approved omega-3 drug indicated for lowering TGs

EPA in the ethyl ester form

Differs from O3AEE that contains both EPA and DHA in the ethyl ester form

Omega-3 Fatty Acids: REDUCE-IT Trial

8,000 Pts at increased risk of CVD TG level was 135 – 499 gm/dL

Study: IPE (Vascepa) combined with statin vs statin alone to prevent events in high risk Pts with mixed dyslipidemia [4 gm/day IPE vs placebo]

Pts had known CVD, or diabetes and at least one other CV risk factor

Followed for 5 years

Omega-3 Fatty Acids: REDUCE-IT Trial

IPE significantly reduced CV events by 25%. All of the following were significantly decreased:

28% (p<.001) CV death, MI or stroke in the secondary prevention population

26% (p<.001) CV death or nonfatal MI

31% (p<.001) Fatal or nonfatal MI

35% (p<.001) Urgent or emergent revascularization

20% (p<.03) CV death

32% (p<.002) Hospitalization or UA

28% (p<.01) Fatal or nonfatal stroke

23% (p<.001) Total mortality, nonfatal MI or stroke

Omega-3 Fatty Acids: REDUCE-IT Trial IPE was a more effective add-on agent to statins for

reducing adverse CVD outcomes in REDUCE-IT than virtually every hypolipidemic drug tested in the last 12 years (including: niacin, Zedia and other fibrates). It was safer with fewer side effects than any of the other test drugs.

The fact that 4 gm/day of IPE was remarkably effective strongly reinforces that dose is important

STRENGTH trial expected in 2020 used 4 gm/day of EPA and DHA (as free fatty acids) will help clarify

Icosapent ethyl (IPE)Was the benefits from lowering TG or are there other cardioprotective properties?

EPA reduces inflammation, LDL oxidation and improves endothelial function

In REDUCE-IT: Omega-3 lowered the high sensitivity C-reactive protein (hsCRP) levels

EVAPORATE Trial Icosapent ethyl (Vascepa, Amarin) 4 g/day vs placebo

in addition to statin therapy (randomized, double-blind, placebo controlled)

80 Pts > 45 y.o (mean age 57) with at least one angiographic stenosis of 20%

Trig levels of 135 – 499 mg/dL, LDL > 40 but < 115 on stable statin Rx

CT angiogram was performed at baseline and 9 mths (final analysis to be at 18 months)

EVAPORATE Trial At 9 months: icosapent ethyl slowed progression of the

primary endpoint of low attenuation plaque by 21% (p=.469 NS) [noncalcified plaque was changed to low attenuation]

Four other endpoints showed slowing of progression:

19% for total noncalcified plaque (p=.01) 42% for total plaque (p=.0004) 57% for fibrous plaque (p=.011) 89% for calcified plaque (p=.001)

EVAPORATE TrialConclusions:

Icosapent ethyl failed to significantly modify the primary endpoint (low attenuated plaque) but did show beneficial effects in secondary endpoints

Probably not a failed trial but a small, underpowered trial with interim analysis at 9 mths. It is felt the 18 mth data will confirm both the primary and secondary endpoints

Omega-3 Fatty Acids November, 2019: FDA (based on the REDUCE-IT trial)

unanimously backed Icosapent ethyl (Vascepa) as a new indication for reducing CV event risk REDUCE-IT used Pts with Trig > 135 but some panel

members suggested > 150 or even 200 mg/dL

Some concern over small incident of AF

Some concern over small but significant risk of serious bleeds (all pts with bleeds were on one or more antiplatelet drugs or anticoagulants)

Dominant treatment: improved Pt outcomes and reduced medical costs

Omega-3 Fatty AcidsIs there an increased bleeding risk?

Theoretically, could increase risk by its effects on arachidonic acid pathway yielding lower production of thromboxane A2 and plasminogen activator inhibitor-1 (PAI-1)

REDUCE-IT: no increase in fatal bleeding, hemorrhagic stroke, serious CNS or GI bleeds in omega-3 group although rates of serious adverse bleeding events trended higher (2.7 IPE vs 2.1% in placebo: NS)

In one trial, the higher level of EPA + DHA the lower the need for perioperative transfusion with CABG (Akintoye et al. Circ Cardiovasc Qual Outcomes. 2018)

Omega-3 Fatty AcidsWhy did prior omega-3 trials fail?

Short intervention duration

Lengthy event-to-enrollment intervals (in secondary prevention trials)

Low omega-3 dose

High background fish intake

Three trials had insufficient statistical power due to lower than anticipated event rates [4,5,6]

Omega-3 Fatty AcidsHow do we assess Pts?

Dietary intake of foods high in omega-3

90% of Americans do not consume the recommended amount of fish and/or omega-3 (Tavazzi et al. Lancet, 2008;372(9645):1223-1230)

Fish rich in omega-3s: salmon, herring, trout, sardines and albacore tuna

Fish with small amounts of omega-3s: cod, catfish, tilapia, scallops, lobster, mussels and shrimp

Following the AHA dietary recommendations, the O3I range was 3.3% to 11.4% which spans the full high to low risk spectrum.

Omega-3 Fatty AcidsPt assessment (cont.):

Direct assessment (preferred): measure the mega-3 Index (O3I) by blood test. Reports the proportion of EPA and DHA in red blood cell membrane fatty acids (as a percent of total fatty acids) target of 8 – 12% to reduce the risk of primary cardiac death (confirmed by research) [7,8]

Testing every 4 – 6 months is better than dietary assessment

Omega-3 Fatty Acids: Conclusions Trials in the last year have changed convention

wisdom

General population with diabetes 1 gm/day of omega-3 fatty acids reduced the risk of both death from CVD and from a MI

High TG on statins, 4 gm/day of IPA decreased the risk of several CVD outcomes including CV death

For primary prevention, at least one to two fish/seafood servings a week

Measuring O3I can monitor efficacy




• Coenzyme Q10

• Red Yeast Rice



Vitamin Supplements 49% of US population takes at least one MVI

More common among women over men

The Physicians Health Study II (PHS II): 14,641 male physicians > 50 y.o. followed for median of 11.2 yrs.

Randomized, double-blind, placebo controlled with a 2x2x2 trial design of: commercial MVI (30 ingredients), Vit E or beta-carotene for prevention of cancer, CVD, eye disease and cognitive function

No significant benefit over placebo for MACE, CV death or total mortality [9)]

(9) JAMA 2012 Nov 7; 308(17):1751-60

Vitamin Supplements MVI did not reduce the risk of total ischemic or

hemorrhagic stroke, CHF, angina or coronary revascularization

The US Preventive Services Task Force (USPSTF) does not recommend the use of MVI for the prevention of cardiovascular disease

Vitamin Supplements: Antioxidants SU.VI.MAX: Randomized, placebo controlled trial

conducted in France

13,017 adults randomized to Vit E, C, beta-carotene, selenium and zinc versus a placebo

7.5 years median follow up

No significant difference for all-cause mortality or ischemic CVD [10]

(10) J Am Coll Cardiol. 2018 May 28; 71(22):2570-84

Vitamin Supplements: Folate Homocysteine is associated with an increased risk for CVD

and Folic Acid can reduce plasma levels

The Aspirin/Folate Polyp Prevention Study: double blind placebo-controlled trial 1121 Pts 21-80 y.o. randomized to folic acid (1 mg/d) vs placebo.

No difference in CVD or all-cause mortality

China Stroke Primary Prevention Trial: 20,702 Chinese adults with HTN but no CVD to enalapril

versus enalapril with folic acid for 4.5 yrs.

Enalapril and Folic Acid group had greater reduction in ischemic stroke and all CV events – more pronounced in Pts with low baseline folate levels (lack of foods fortified with folic acid in China) [11] JAMA 2015

Vitamin Supplements: Vitamin E The PHS II and SU.VI.MAX evaluated Vit E with other

vitamins and antioxidants and found no significant CV improvement

The Women’s Health Study randomized 39,786 health women to Vit E or placebo over 10.1 years

Fewer MACE in Vit E group but did not reach statistical significance

CV death was lower in the Vit E group – possibly due to the differences of Vit E in women over men

Vitamin Supplements: Vitamin E The Heart Outcomes Prevention Evaluation (HOPE)

randomized 9,541 Pts to ramipril vs placebo and Vit E vs placebo (Vit E arm was extended four years into HOPE-TOO) – no significant difference in Mace or overall mortality

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) randomized Vit E vs Vit E plus selenium vs placebo

All-cause mortality, CV events, CV deaths did not significantly differ from placebo in Vit E arm

Vitamin Supplements: Niacin♥ Atherothrombosis Intervention in Metabolic

Syndrome with Low HDL/High Triglycerides (AIM-HIGH) trial randomized 3,414 Pts with known CAD to extended-release niacin or placebo

♥ HPS2-THRIVE trial randomized 25,673 Pts with know CAD to niacin-laropiprant or placebo

Both showed no difference in MACE but niacin group had increased adverse events

Vitamin Supplements: Beta-Carotene ATBC and CARET trials evaluated beta-carotene in Pts

at high risk of developing lung cancer and both trials found an increased risk of lung cancer in patients taking beta-carotene

The USPSTF recommends against the use of beta-carotene for cancer prevention or CV disease

Vitamin Supplements: Problems Niacin – flushing and liver abnormalities

Beta-carotene can cause hypercarotenemia or yellowing of the skin

MVI can cause rashes and minor bleeding

Selenium can cause GI symptoms

Excessive Vit A in postmenopausal women have been associated with increased hip fractures [JAMA 2002 Jan 2;287(1) 47-54]

Vitamin Supplements Conclusion:

MVI, Vit E, Vit C, beta-carotene, selenium, zinc, folate and niacin have all failed to show a significant CV benefit (except in circumstances of low dietary intake)

May be harmful with certain side effects




• Coenzyme Q10

• Red Yeast Rice



Coenzyme Q10 Cofactor for mitochondrial involved oxidative

phosphorylation producing ATP

Other functions include cell signaling, gene expression and membrane stabilization

It is synthesized in the body (not a vitamin that must be obtained through diet) however, endogenous biosynthesis declines with age

Tissue CoQ10 may be compromised in pathophysiologic states

Coenzyme Q10

200mg BID with meals has been shown to obtain a therapeutic blood level of > 2.5 mcg/mL (trials: 100-400mg daily)

Ubiquinol form of CoQ10 has greater bioavailability over the oxidized form of ubiquinone

Side effects (mild): decreased appetite, diarrhea, dizziness, dyspepsia and N/V

Does not affect warfarin levels

Coenzyme Q10 Statin-Associated Muscle Symptoms (SAMS):

Minor to severe muscle aches to pain and cramps, muscle weakness and rarely rhabdomyolysis

More common in women and older adults

Statins inhibit mevalonate pathway which also produces compounds for normal mitochondrial function (to include CoQ10)

Studies have documented reduction of CoQ10 in blood and tissues such as the heart and liver

Mitochondrial dysfunction is hypothesized as the cause of SAMS

Coenzyme Q10 and SAMS Studies of CoQ10 and SAMS (Statin-Associated Muscle

Symptoms ):

Toth et al (2017): 105 Pts randomized to statin, statin + CoQ10(200mg/QD), statin + CoQ10 + omega-3. The group with CoQ10 had significantly less myalgia, MM weakness and cramps than the other two [12]

Bookstaver et al(2012): 76 Pts with SAMS to CoQ10 (60mg BID) vs placebo. Reduction in SAMS in both groups (no statistically significant difference)[13]

Coenzyme Q10 and SAMS Taylor et al: 120 Pts with presumed SAMS using a

double cross over study showed only 1/3 (41 Pts) developed myalgia on simvastatin but not with placebo (Dx of SAMS may be problematic)[14]

The 41 Pts with “confirmed” SAMS were then randomized to CoQ10 (600mg/d) versus placebo. More Pts reported pain on CoQ10 than on placebo

Coenzyme Q10 and SAMSMeta-analysis:

Banach (2015): 253 Pts (meta-analysis) did not suggest a benefit with CoQ10 for SAMS [15]

Qu et al (2018): 575 Pts in 12 randomized controlled trials show CoQ10 significantly ameliorated SAMS [16]

Muscle pain (p<.001)

Muscle weakness (p=.006)

Muscle fatigue (P<.001)

Coenzyme Q10 SAMS Summary:❖If a reasonably certain Dx – stop statin for 1 month and

restart another statin at a lower dose.

❖If symptoms return, add CoQ10 at 200-400mg QD (ubiquinol in water-soluble softgel). It is reasonable to stop the statin and allow symptoms to resolve before dual therapy.

❖If symptoms of SAMS recur but are milder, continue both. If severe then stop both.

❖[Could be considered Class Recommendation IIa]

Coenzyme Q10 and CHF In CHF, Pts have measurable deficiencies of CoQ10 in

blood and myocardial tissue

Fotino et al.(2013): meta-analysis of 13 studies with 395 Pts. Supplemental CoQ10 resulted in a pooled mean net change in EF of 3.67%. The study suggested the benefit may be limited to Pts with less severe CHF: EF > 30% Or NYHA Class II or III symptoms [17]

Jafari et al. (2018) looked at 71 trials lasting at least 3 months and found a “discordance of findings” but did note a strong safety profile of CoQ10 [18]

Coenzyme Q10 and CHFQ-SYMBIO trial: prospective, randomized, controlled multicenter trial had 420 Pts given CoQ10 100mg TID and follow up of two years: [19]

At 16 weeks: improvement in NYHA class and six minute walk tests in both the CoQ10 and Placebo groups. NT-proBNP levels were not statistically different

At 2 years: CoQ10 group had: 43 % reduction (p=.005) in deaths, hosp. and need for LVADs (n=30,

15%) vs Placebo (n=57, 26%)

43% reduction (p=.039) in CV deaths

Reduced hosp. (CoQ10 17.8% vs Placebo 14%)

Significant improvement in NYHA class

Improvement in EF only if with baseline EF > 30%

Mortensen et al. JACC Heart Failure 2014 Dec; 2(6):641-9

Coenzyme Q10 CHF Summary:

❖CHF with EF > 30% consider CoQ10 as add on therapy after proven therapy (ACE/ARB, Beta-blocker and spironolactone)

❖Cardiologist specializing in advanced HF management do not advocate the routine use of CoQ10

❖[Class Recommendation: IIb]




• Coenzyme Q10

• Red Yeast Rice



Red Yeast Rice❖Created by fermenting yeast in red rice which

produces a complex of substances called monacolins

❖One subtype is monacolin K which is structurally identical to lovastatin and it inhibits HMG-CoA reductase (rate-controlling step in cholesterol synthesis)

Red Yeast Rice: Efficacy❖ Gerard et al.: Meta-analyses of 20 studies with RYR with

doses between 1,200mg 4,800mg daily (4.8mg to 24mg monacolin K) [20]

Reduced LDL-C by 39.4mg/dL after 2-24 months (compared to placebo)

Same reduction as pravastatin 40mg and lovastatin 20mg

Also saw a small increase in HDL-C and lower Trig over placebo

[20] Gerald et al.: Atherosclerosis 2015; 240(2):415-23.

Red Yeast Rice: Efficacy Li et al.: Studied 1,445 patients 65-75 y.o. with prior MI

to RYR over a 4 year period with reduction over placebo: [21] 31% CHD

31.9% all-cause mortality

44.1 % Stroke

48.6% CABG or PCI

51.4% malignancies

29.2% CHD death (6.4% with RYR, 9% placebo) but this was not a primary end point (51 pts over 4 years to prevent one death)

Red Yeast Rice

❖RYR can interact with other natural products (having different mechanisms of action) resulting in a synergistic effect. These include: policosanols, berberine, plant sterols, artichoke and silymarin.

❖Most are small trials showing varying reductions in LDL-C in the 18 – 33% range

Red Yeast Rice: Safety CYP450 inhibitors (grapefruit juice, cyclosporine etc.)

can increase levels of monocolin K and cause muscle symptoms

Even with chronic use, these effects are generally safe and well tolerated

Exception: citrinin (mycotoxin metabolite derived from Monascus fermentatio) can be nephrotoxic, embryo toxic and cause renal tumors. Max dose of 20 ug/Kg/day can be ingested without nephrotoxicity (but genotoxic or carcinogenic effects cannot be excluded with certainty).

Red Yeast Rice: Summary RYR extract is the most effective nutritional

supplement for lowering cholesterol

RYR efficacy is proportional to its content of monacolin K

Combination of RYR and other natural products with different mechanisms of action may have a synergic effect for lowering cholesterol levels

RYR has a high tolerability profile (if no citrinin)




• Coenzyme Q10

• Red Yeast Rice



Inorganic Nitrate Supplements Nitric oxide (NO) is a signaling molecule essential to

CV health

NO levels can be increased with foods high in nitrate and the NO produced can support NO synthase

Evidence (small trials) suggests that nitrate supplementation can help regulate BP, limit atherosclerosis and improve cardiac contractility in both healthy and those with CV disease

Prophylactic level of inorganic nitrate (300-800 mg/d) can be obtained with fruits and vegetables with high nitrate content or commercial nutritional supplements




• Coenzyme Q10

• Red Yeast Rice



Vitamin D and Calcium❖Vitamin D (calcitriol) precursors:

D2 (obtained from plants)

D3 produced after skin is exposed to UVB radiation

❖ Both D2 and D3 can be obtained as dietary supplements. “Vitamin” is a misnomer since the body can produce its required D3 if enough sunlight is provided, however, endogenous production is often insufficient.

❖ D2 and D3 are hydroxylated in the liver to form Vit D which is the primary circulating form of Vitamin D

Vitamin D and CalciumCirculating 25(OH)D concentration is the marker of choice for Vit D activity

< 12 ng/mL = frank deficiency

12-20 ng/mL = insufficient for optimal bone health

“Optimal level” is controversial

Vitamin D and CVD Early ecologic studies showed that distance from the

equator and seasonal changes (producing less sunlight) was associated with increased CV risk [22]

NHANES III lowest quartile of 25(OH)D < 17.8 ng/mL had a 26% all-cause mortality compared to the highest quartile after adjustment for other factors [23]

Observational studies are innately limited

Vitamin D and CVD Earlier randomized clinical trials have focused on bone

health as primary outcome and had mixed finding regarding CVD

Two recent trials have high-quality evidence:

ViDA Study: New Zealand with 5,000 residents age 50-84 y. o. were given placebo vs 200,000 IU initially followed by 100,000 IU monthly for a median of 3.3 yrs

VITAL trial (Vit D and Omega-3 Trial): 25,871 US Pts (with 5,106 African Americans), men > 50 y.o and women > 55 y.o were given placebo or 2,000 IU daily for median of 5.3 yrs.

Vitamin D and CVD ViDA study: serum 25(OH)D increased to more than

20 ng/mL but no significant improvement in CV events [24]

VITAL study: Primary outcome of MI, stroke, CV death and found no significant benefit to CVD (independent of race) [25]

Women’s Health Initiative Calcium and Vitamin D trial also found no CV benefit [26]

Vitamin D Safety Acute Vit D toxicity could be life threatening but it is

rare with supplementation and requires extremely high doses

Vit D toxicity is associated with hypercalcemia and low serum parathyroid levels. Sx: “stones, groans, thrones, muscle tones and psychiatric overtones” for nephrolithiasis, abdominal symptoms (pain, anorexia, N/V), polyuria and polydipsia, hypotonicity and hyporeflexia and neuropsychiatric issues

> 10,000 IU/day is required for acute toxicity

Vitamin D Safety Meta-analysis for Vit D plus calcium (not Vit D alone)

found increased risk for stroke [27]

Increased susceptibility to kidney stone formation has been reported [28]

[27] Khan et al: Ann Intern Med. 2019 Aug 6; 17(3):190-198[28] Jackson et al: NEJM 2006 Feb 16; 354(7):669-83

Vitamin D and Calcium Safety Bolland et al. (2010) found a 27% increase in the risk of

MI in women taking calcium supplements

These findings proved controversial via other studies

Vit D and calcium role in fracture reduction has been questioned by recent studies. The US Preventive Services Task Force gave only an “Insufficient” recommendation for fracture reduction in the general population

Vitamin D and Calcium Summary: Despite an association between serum 25(OH) D

deficiency and higher mortality and CVD, no clear benefits have been seen in randomized controlled trials.

25(OH)D levels should not be routinely tested and vitamin D supplements should not be prescribed or recommended for preventing CVD events.

Recommend healthy diet and active lifestyle

There is no convincing evidence of CV harm, so supplementation for other indications is reasonable




• Coenzyme Q10

• Red Yeast Rice



william bowden, do, facc january 22, 2020 · amount of fish and/or omega-3 (tavazzi et al. lancet,...

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