Aids HIV FAQ

Ravnskov "Cholesterol Myth" Website (the Lipid Hypothesis of Atherosclerosis)

Question:

(Anthony Brea D.C.) writes: >Are you going to argue that every one of the treatments above >works to lower coronary disease by some other mechanism than by >lowering cholesterol, even though that’s what they were all designed

to >>do, and that is what they actually do?  That’s quite a coincidence. >>Which is my point. >I understand your point. And I don’t consider it to be such a

coincidence since the factors that lead to MI’s are numerous and that these numerous >factors are obviously biochemically interactive.     But we didn’t pick any of these therapies, from corn oil to niacin to liver transplant to statin drugs to bile acid binders, to target any of those other myriad causes of heart disease.  We just did all the things we could to lower cholesterol.  And they all work if they do that (as does feeding less cholesterol to monkeys or rabbits, if we’re doing it THAT way).  Now, I’m supposed to believe that every last one of these treatments of the organism has another biochemical effect, besides the one on cholesterol, which just happened to help the disease I’m aiming at?  And that the effect happens to be proportional to how much the cholesterol changes, even though the effects are all different, and not related?  That’s not a smart bomb you’re talking about, there. That’s serendipity of divine proportions.  Like, we’re talking angels on the scientist’s shoulders.  You should really be building a church with this theory.  The folks who could not miss when they aimed at disease.  The dumb schmucks hit it every time, notwithstanding that their main theory for aiming was wrong in every case.  Wow. >In addition non of these mechanisms niacin, statin, corn oil,

vegetarian >diets etc.. have singular effects. Non of them function as SMART bombs. And >we all know about collateral (damage) effects. Consider the numerous >metabolic changes associated with shifting from a highly refined high fat >diet to a low fat vegetable based whole food diet. I would hope you would >agree that that dietary change is not just about fats. >And yes, that is almost what I’m going to do. Let me clarification. I

will argue that ‘most’ of these treatments lower coronary disease and/or >coronary disease related deaths by a multiple number of mechanisms which possible include ‘lowering cholesterol’, even though they were all designed >to lower cholesterol.<    They all lower coronary events if they lower cholesterol significantly.  ALL of them.   And the more they lower it, the better they work, whenever that data is available. > Non of these therapies just lower cholesterol. And >although lowering cholesterol ‘may be’ a significant factor it is >clearly not the only one or necessarily the most important one.

   Only if you believe in the Yankees.                                  Steve Harris, M.D.

Response:

> Bacteria could be involved, directly or indirectly by causing: > The bottom line is that it does *NOT* appear that you *ONLY* get > clogged arteries from high cholesterol *AND* Chlamydia:  it is a > complex interaction of a number of factors.

  Can I point people in another direction?  Look into focal infection theories regarding heart disease and root canals – Root Canal Cover-Up Exposed by Dr. George Meinig is fascinating and indicates another whole source of the role of bacteria in heart disease.

Response:

This has got me wondering… Could there be a connection between allergies and heart disease? >Bacteria could be involved, directly or indirectly by causing: >1.  local destruction of the endothelium >2.  endothelial damage due to circulating endotoxin >3.  autoimmunity (Hsp60 cross-reactivity with bacterial antigens) >4.  systemic inflammation with increased C-reactive protein, >leukocytes, and cytokines

Change that to: 1.  endothelial damage due to circulating allergen, or     allergen/antibody complex. 2.  endothelial damage due to histamine. 3.  autoimmunity (Hsp60 cross-reactivity with allergens). 4.  systemic inflammation with increased C-reactive protein,     leukocytes, and cytokines. Not too many changes to that list there… Anyone care to comment? Am I crazy for even thinking along these lines? This theory is scary if true…

Response:

– Hide quoted text — Show quoted text -> And yes, that is almost what I’m going to do. Let me clarification. I will > argue that ‘most’ of these treatments lower coronary disease and/or > coronary disease related deaths by a multiple number of mechanisms which > possible include ‘lowering cholesterol’, even though they were all designed > to lower cholesterol. Non of these therapies just lower cholesterol. And > although lowering cholesterol ‘may be’ a significant factor it is clearly > not the only one or necessarily the most important one. >Okay, let’s turn it around. How do *you* explain the vastly increased >incidence of heart disease in individuals with familial >hypercholesterolemia? >The common forms of familial hypercholesterolemia are due to lack of, or >defective, LDL receptor, resulting in markedly increased LDL cholesterol >levels. Genetic studies indicate that this is the only mutation in the vast >majority of these patients. >The standard theory is: high serum cholesterol => arterial damage => heart >disease.  A single mutation that reduces or prevents removal of LDL >cholesterol from circulation is strongly associated with heart disease. The >standard theory explains this quite neatly. In order to considered >reasonable, your theory needs to do the same.

As well as explain why these kids do okay, with less increase in coronary disease, if given a new liver (which gets LDL levels down).

Response:

With regard to Simvastatin drug, I’ve taken several course of Socor to lower my cholesterol (from 7 to 5).  But I’ve recently heard of another (claimed to be the latest ‘wonder’ drug) called something ‘Lipidor’.  However, I cannot find any info. on it yet.  Can anybody tell me more of its goods and bads or point me in the right directions to find more about this drug.  Thanks. Calvin

Response:

(Anthony Brea D.C.) writes:

Harris: [Besides with two statin drugs, the] >The problem is that the [anti-CAD effect] has >previously been seen ALSO with cholesterol lowering with corn oil >feeding, low fat diets, and surgical bowel bypass; as well as >drug therapy with resin binders, clofibrate, and niacin. >What type of low fat diets are you talking about? Vegetarian? >Anthony B

   Ornish, which is close.  I do wish you’d stop trying to side track us.  Are you going to argue that every one of the treatments above works to lower coronary disease by some other mechanism than by lowering cholesterol, even though that’s what they were all designed to do, and that is what they actually do?  That’s quite a coincidence. Which is my point.                                      Steve Harris, M.D.

Response:

> And yes, that is almost what I’m going to do. Let me clarification. I will > argue that ‘most’ of these treatments lower coronary disease and/or > coronary disease related deaths by a multiple number of mechanisms which > possible include ‘lowering cholesterol’, even though they were all designed > to lower cholesterol. Non of these therapies just lower cholesterol. And > although lowering cholesterol ‘may be’ a significant factor it is clearly > not the only one or necessarily the most important one.

Okay, let’s turn it around. How do *you* explain the vastly increased incidence of heart disease in individuals with familial hypercholesterolemia? The common forms of familial hypercholesterolemia are due to lack of, or defective, LDL receptor, resulting in markedly increased LDL cholesterol levels. Genetic studies indicate that this is the only mutation in the vast majority of these patients. The standard theory is: high serum cholesterol => arterial damage => heart disease.  A single mutation that reduces or prevents removal of LDL cholesterol from circulation is strongly associated with heart disease. The standard theory explains this quite neatly. In order to considered reasonable, your theory needs to do the same. — Mark Brandt, Ph.D. My opinions are my own, but I tend to give them away to anyone who fails to flee fast enough.

Response:

– Hide quoted text — Show quoted text – >writes: >Could you address the issue of bacterial infection, specifically >Chlamydia pneumoniae (I think I spelled that wrong somewhere), acting >as >an intermediate or mediating agent between cholesterol and heart >disease? That you only get clogged arteries from high cholesterol *if* >you are infected with the bug, because it’s the bug that somehow >causes >the cholesterol to deposit on the blood vessel walls? Thanks. >   A theory unproved until we have intervention trials (prospective >randomized studies, as for cholesterol).  I know they are going on, >because one of my coronary disease patients recently enrolled, and got >(in addition to what I was giving him), either placebo or 3 or 4 weeks >of a macrolyde antibiotics (Zithromax, I think).

Important steps in coronary artery disease are damage to the vessels of the heart, plaque formation, plaque rupture and thrombus formation Animal models suggest that mild chronic endothelial damage is potentiated by high cholesterol, products formed by high levels of blood glucose, complexes formed by the immune system, infection and tobacco smoke (and other things). Bacteria could be involved, directly or indirectly by causing: 1.  local destruction of the endothelium 2.  endothelial damage due to circulating endotoxin 3.  autoimmunity (Hsp60 cross-reactivity with bacterial antigens) 4.  systemic inflammation with increased C-reactive protein, leukocytes, and cytokines Chlamydia pneumoniae is a bacteria that has been associated, weakly right now, with coronary heart disease (Lancet 1997;350:430-36).   While all these postulated mechanisms may (or may not) be interesting, what is really important in my opinion is what can be done to stop (or reverse) the process so people live longer and hopefully better lives. Proper diet, sensible exercise, smoking cessation and many other common sense things should be considered first.  However, drugs that lower cholesterol can help some people.  Whether or not antibiotics can help people is being tested (as Dr. Harris mentioned) in the Weekly Intervention with Zithromax in Recurrent Disease trial (WIZARD trial) in people who have suffered a heart attack. The bottom line is that it does *NOT* appear that you *ONLY* get clogged arteries from high cholesterol *AND* Chlamydia:  it is a complex interaction of a number of factors.

Response:

Much snipped: >    I present some of these studies below.  Cholesterol in the > blood in the form of LDL isn’t the only cause of coronary > disease, but it’s a major one, and many routes of evidence point > to its role.  Evidence now beyond a reasonable doubt. >                               Steven B. Harris, M.D.

Could you address the issue of bacterial infection, specifically Chlamydia pneumoniae (I think I spelled that wrong somewhere), acting as an intermediate or mediating agent between cholesterol and heart disease? That you only get clogged arteries from high cholesterol *if* you are infected with the bug, because it’s the bug that somehow causes the cholesterol to deposit on the blood vessel walls? Thanks.

Response:

writes: >Could you address the issue of bacterial infection, specifically >Chlamydia pneumoniae (I think I spelled that wrong somewhere), acting as >an intermediate or mediating agent between cholesterol and heart >disease? That you only get clogged arteries from high cholesterol *if* >you are infected with the bug, because it’s the bug that somehow causes >the cholesterol to deposit on the blood vessel walls? Thanks.

   A theory unproved until we have intervention trials (prospective randomized studies, as for cholesterol).  I know they are going on, because one of my coronary disease patients recently enrolled, and got (in addition to what I was giving him), either placebo or 3 or 4 weeks of a macrolyde antibiotics (Zithromax, I think).                                       Steve Harris, M.D.

Response:

(Anthony Brea D.C.) writes: > Statin drugs >    1) lower cholesterol >    2) reduces vascular reponse to stress >    3) reduces the viscosity of the blood >    4) reduces plasma fibrinogen levels >    5)  reducesred cell aggregation   >    6) plasma viscosity >    7) improves fasting insulin (hyperinsulinemia. Syndrome X) >    8) inhibit vascular smooth muscle migration and proliferation >The point of the above is that these drugs don’t just "lower cholesterol." >Anthony B

COMMENT:    Look, this thread is beginning to remind me strongly of the arguments that AIDS is not caused by HIV.  The skeptics in that case instead had a long list of things they said caused AIDS instead, and that was coincidence #1: all this other stuff only started to cause AIDS after 1980 or so, shortly after HIV showed up from Africa (1976-8).  Coincidence #2 was that HIV status correlated the best of any single factor with risk for AIDS (about 100%), but the skeptics had such a long list of other putative causes, they could explain ALL the AIDS cases with SOMETHING that wasn’t HIV.    There were animal models of AIDS with a closely related virus called SIV.  Skeptics said it wasn’t AIDS, or that SIV wasn’t closely related enough.    Then a drug came out that suppressed HIV, and it made AIDS patients live longer.  Wups.  The skeptics called the study fraud, and said the AZT group also got Bactrim, which really did the job.  Then they said the AZT had been shared, so it really killed the placebo folks.  Then they said AZT helped people by other mechanisms, chiefly by getting them transfused and taken better care of.  Then they said the TOTAL mortality was greater in the AZT group after a while (which it was, due to AZT toxicity), so that even though AIDS deaths were first down with AZT, then unchanged as the virus resistance built up, maybe some deaths that should be AIDS were being chalked up to accident and suicide that shouldn’t have been.  So AZT really wasn’t helping AIDS at all.    Okay, then came the protease inhibitors, drugs specifically targeted and engineered to one HIV enzyme— the viral protease. They also helped AIDS and cut death rate in half when added to AZT class drugs.  Proof at last!  But now the skeptics said that proteases weren’t just working on HIV, but were general immune boosters and AZT detox agents too.  Then they said they made people ill and go off all drugs, and THAT was helping their AIDS.   Gosh, it seemed impossible to develop a drug against HIV without finding that– by serendipity! — it also helped AIDS by another unsuspected mechanism.  So AIDS wasn’t anything to do with HIV. Anything to avoid having to admit that, though many people still took the proteases (and had come back from the edge of death with their help).  Their HIV was being killed, but that, we were told by skeptics, was a side  effect.  Too bad other drugs tried which hadn’t been developed against HIV weren’t doing as well against AIDS.  Back luck, no doubt, since there was no reason that working against HIV gave a drug any special advantage…..     I hope you see the parallel.  Scientific theories are impossible to prove, notes philospher K. Popper, because you can always explain any result by a different (albeit more complicated) theory.  In fact, the horrible truth is that scientific theories which have rabid backers are impossible to DIS-prove with new data, pace Dr. Popper, because what happens is that people with pet theories change them and complicate them and jigger them up to fit new data as it comes along.  They can do that forever.  But at some point the old theories simply become too ugly and complicated to believe, and that’s when science changes its mind.  Not the die-hards, of course.  Max Planck, discoverer of the quantum of energy, always said that science changes only because old profs die, and new ones come into power who believe new ideas.  And so, Planck noted dryly, science progresses, funeral by funeral.    The lipid hypothesis of coronary heart disease was developed from epidemiological correlation.  Skeptics said it was just correlation, and a multitude of other factors explained athero- sclerotic coronary heart disease better.  Then animal models showed you could turn heart disease on and off by feeding cholesterol.  Skeptics pointed out it had to be oxidized cholesterol.  Scientists showed then you could do it with saturated fat and that most cholesterol in the diet of humans had oxidized cholesterol in it anyway.  Skeptics pointed out that animals weren’t humans.  And so it went.     Then drugs which lowered cholesterol were proven to decrease placque size in hearts, and lower MI risk.  Skeptics have always said that each class of drugs which does this,  has other benefits on the heart and vessels.  You’re recently done his with simvastatin and pravastatin.   The problem is that the effect has previously been seen ALSO with cholesterol lowering with corn oil feeding, low fat diets, and surgical bowel bypass; as well as drug therapy with resin binders, clofibrate, and niacin.  Total deaths were decreased with niacin, and even in the other trials, increases in total deaths (due to non heart deaths) were not necessarily evidence against the cholesterol hypothesis of coronary disease.    I present some of these studies below.  Cholesterol in the blood in the form of LDL isn’t the only cause of coronary disease, but it’s a major one, and many routes of evidence point to its role.  Evidence now beyond a reasonable doubt.                               Steven B. Harris, M.D. Am J Cardiol 1996 Sep 26;78(6A):13-19   Review of the major intervention trials of lowering coronary artery disease risk through cholesterol reduction. Stark RM Yale University School of Medicine, New Haven, Connecticut, and Greenwich Hospital, Greenwich, USA. Results of primary and secondary prevention trials have shown that lowering total cholesterol and low-density lipoprotein (LDL) cholesterol leads to a reduction in both fatal and nonfatal ischemic events. The reduced coronary artery disease (CAD) risk associated with cholesterol lowering appears to be unrelated to the intervention used, whether it be a low-fat/low-cholesterol diet, partial ileal bypass surgery, or pharmacologic intervention with an agent such as a bile resin, a fibrate, or niacin. Data emerging on the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have shown that this newest class of cholesterol-lowering agents also reduces the risk for CAD. The studies provide increasing evidence that high LDL cholesterol levels not only contribute to atherosclerotic plaque formation but also interfere with normal endothelial control of arterial vasomotor tone. Because the small amount of plaque regression observed on angiographic studies is not sufficient to explain the magnitude of CAD risk reduction associated with lowered levels of LDL cholesterol, these studies suggest that vasomotor control and plaque stabilization may have a greater impact on clinical events than the stenosis caused by atherosclerotic plaques. Publication Types:   Review   Review, tutorial Am Heart J 1994 Dec;128(6  Pt 2):1344-1352   Nonpharmacologic therapy for coronary artery atherosclerosis: results of primary and secondary prevention trials. Amsterdam EA, Hyson D, Kappagoda CT Department of Internal Medicine, School of Medicine, University of California, Davis. The association between abnormal serum lipoprotein levels and coronary atherosclerosis has been established by extensive clinical, experimental, and epidemiologic evidence. Recent angiographic trials in patients with coronary artery disease have demonstrated that improvement in serum lipids and other risk factors has a favorable effect on coronary lesions and reduces coronary events and interventions. Most trials of coronary disease prevention have used intensive pharmacologic therapy, but several have involved only nonpharmacologic intervention. The latter investigations include both primary and secondary prevention studies. Three controlled, nonpharmacologic primary prevention trials with long-term follow-up used dietary management aimed at lowering serum cholesterol levels; one trial also included smoking cessation, and one used a comprehensive approach to risk-factor modification. Serum cholesterol levels and other risk factors were significantly decreased in the intervention groups but were unaltered in the control populations. After periods of 5 to 10 years, reductions of 20% to 45% in coronary events were observed in the intervention groups compared with controls. Four secondary intervention trials examined the effect of nonpharma- cologic therapy alone on coronary artery disease regression; three of these trials included control groups. All of the trials focused on reduction of elevated serum cholesterol levels with a low-fat diet, and several included interventions for other risk factors. Serum cholesterol levels fell by 14% to 24% in treated patients compared with 4% to 9% in controls. Although these trials were of relatively short duration (1 to 3 years) and included small numbers of patients (36 to 90), each demonstrated favorable effects on coronary lesions and three revealed clinical benefits. Publication Types:   Review   Review, tutorial Coron Artery Dis 1995 Jun;6(6):457-465   Clinical investigations of the arrest and reversal of coronary artery disease. Farmer JA, Gotto AM Jr Section of Cardiology, Ben Taub General Hospital, Houston, Texas, USA. Trials of lipid-lowering therapy with angiographically monitored endpoints have demonstrated that regression of atherosclerosis can be achieved. Additionally, the unexpected clinical benefit seen in some trials has suggested that stabilization of … read more »

Response:

>Please supply citations to these ’simvalstatin’ and pravachol’ trials.

Okay– I’ll do that and more. Below, we start with the original classic "4S Trial," the first of its kind with the new cholesterol-lowering class of drugs called HMG-CoA reductase inhibitors, the first of which was Mevachor, a drug ultimately derived from a fungus.  The related drug in this trial is called simvastatin ("Zocor"). In following messages, I’ll post a few articles and reviews discussing the implications of the lipid hypothesis in light of these trials, as well as some reviews of earlier trials, and a discussion of the question of possible danger from low blood cholesterol.  Since we’re still having some of this nonsense about the idea that high blood cholesterols don’t contribute to heart disease, this is all worth while to put up again.   Obviously cholesterol isn’t the whole story, but there’s no question that risk of dying can be manipulated by lowering cholesterol, in people whose cholesterols are too high.  That’s the answer we need to know.                                Steve Harris, M.D. Lancet 1994 Nov 19;344(8934):1383-1389   Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo. Over the 5.4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprot- ein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0.66 (95% CI 0.59-0.75, p < 0.00001), and the respective probabilities of escaping such events were 70.5% and 79.6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatm- ent included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularisation procedures. This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients. Publication Types:  Clinical trial  Randomized controlled trial Comments:   Comment in: Lancet 1994 Dec 24-31;344(8939-8940):1767-8   Comment in: Lancet 1995 Jan 28;345(8944):264   Comment in: Lancet 1995 Mar 4;345(8949):592   Comment in: ACP J Club 1995 May-Jun;122(3):66-7   Comment in: Lancet 1995 Jul 15;346(8968):181-2   Comment in: Lancet 1996 Feb 24;347(9000):551 PMID: 7968073, UI: 95057659 Arch Intern Med 1996 Oct 14;156(18):2085-2092   Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study. Pedersen TR, Berg K, Cook TJ, Faergeman O, Haghfelt T, Kjekshus J, Miettinen T, Musliner TA, Olsson AG, Pyorala K, Thorgeirsson G, Tobert JA, Wedel H, Wilhelmsen L University of Oslo, Norway. BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent. Publication Types:  Clinical trial  Randomized controlled trial PMID: 8862101, UI: 97015420 COMMENT: The above is a secondary prevention trial, meaning it was done on people already known to have heart disease.  The most famous *primary* prevention trial (meaning it was done on people with no symptoms or known disease, but just high cholesterols), using the new class of drugs, is the "West of Scotland Coronary Prevention Study."  This study used pravastatin ("Pravachol"), a related drug to the simvastatin used in the study above: N Engl J Med 1995 Nov 16;333(20):1301-1307   Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ Department of Pathological Biochemistry, University of Glasgow, Scotland. BACKGROUND. Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. METHODS. We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. RESULTS. Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). CONCLUSIONS. Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction. Publication Types:  Clinical trial  Randomized controlled trial Comments:   Comment in: N Engl J Med 1995 Nov 16;333(20):1350-1   Comment in: ACP J Club 1996 Mar-Apr;124(1):40   Comment in: N Engl J Med 1996 May 16;334(20):1333; discussion 1334-5 PMID: 7566020, UI: 96036646

Response:

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