STATIN Drug Risk vs Benefit

There is a war going on in the medical trenches that you may be unaware of . . .

The role your cholesterol plays as the cause of heart disease and stroke has been the source of ongoing controversy and contention for decades. In fact, it is the the reason the a nasty phone call I’ve received from local cardiologists attempting to chew me out in front of my patient for not putting him on a STATIN drug or using the latest PCSK9 inhibitor (the cholesterol shot) to treat his risk for heart disease and stroke.

The war, now fought between our medical offices, is between the advocates (pharmaceutical companies and a plethora of cardiologists) who view high cholesterol as the causal factor in vascular disease and the skeptics who consider cholesterol an essential fuel and vital component of cellular metabolism. The main argument of the advocates is the presence of cholesterol in atherosclerotic tissues and studies that demonstrate an association of cholesterol in the calcified tissue of the blood vessels.

The skeptics on the other hand (I am a very vocal skeptic) have emphasized that a comprehensive review of the medical literature reveals a lack of evidence of a causal link between cholesterol and heart disease and strokes. The absence of cholesterol in those with a high degree of atherosclerosis was first described in 1936. Additionally, the fact that older adults with low levels of cholesterol with just as much atherosclerosis as those with high levels of cholesterol also plays into this argument [1,2].

The fact that high cholesterol is NOT a risk factor in coronary heart disease (CHD) has been documented in numerous studies in a very broad range of people including women, Canadian men, Swedes, Maoris, the elderly and patients with CHD. [3,4,5,6,7].

Despite the extensive research demonstrating that heart disease and stroke occur independently of cholesterol levels, the advocates of the cholesterol hypothesis are winning the war. The advocates have praised STATINs as “miracle drugs” which are “the best anti-atherosclerotic insurance” and the “most powerful inventions to prevent cardiovascular events” [9, 10]. The have also promoted the view that “there are no longer any doubts about the benefits and safety of reducing cholesterol levels” [11].

Because of these statements, today millions of people are on STATIN medication, drugs that reduce the cholesterol levels by inhibiting and enzyme called HMG-CoA reductase. And, the number of healthy people currently on STATIN medications will increase considerably if the 2018 guidelines from the American College of Cardiology and the American Heart Association are continually followed [8].

However, the skeptics have acknowledged that STATIN treatment has been shown to reduce coronary events, but close inspection of the research reveals that the benefit is MUCH LESS impressive than clinicians and the general public have been told and that it must be because of other mechanisms (pleiotropic effects of statins) than just cholesterol reduction [2, 12, 13, 14].

What I have found in my extensive review of the cholesterol literature, and my 20+ years of clinical practice, is that the beneficial effects on CVD are actually miniscule and that their adverse effects are more common than is generally admitted or known.

The appearance of impressive effects of these STATIN drugs is created through the exploitation of a statistical anomaly called relative risk, and by designing and interpreting studies in a way to minimize the appearance of adverse effects [15]. The war on cholesterol has been fought using this statistical deception to create the appearance that STATINs are wonder drugs, when in reality, their trivial benefit is more than offset by their adverse effects.

In order to understand how effects of STATINs on coronary artery disease and stroke have been misrepresented in clinical research, it is important to understand some terms. The statistical terms you need to focus on are relative and absolute risk, relative and absolute risk reduction (ARR) and the number needed to treat (NNT).

How to Determine Absolute and Relative Risk Reduction

To explain the use of these terms in clinical research, consider a 5-year clinical study that includes 2000 healthy, middle-aged men just over the age of 50. The aim of the study is to see if a STATIN can prevent heart disease. Half of the participants are given the STATIN drug and the other half are given a placebo. In general, you can see that during a period of 5 years about 18% of all healthy, middle-aged men experience a nonfatal myocardial infarction (MI), a heart attack that does not cause death. Consequently, at the end of this hypothetical trial, 18% of the placebo-treated men and 17% of the statin-treated men suffered an MI. Statin treatment, therefore, has been of benefit to 1% of the treated participants. Thus, the ARR, which quantifies how effective a treatment is on the population at risk, was one percentage point, and the NNT was 100, resulting in only 1 of 100 people benefiting from the treatment. Put another way, the chance of not suffering from an MI during the 5-year period without treatment was 98% and by taking a statin drug every day it increased by 1 percentage point to 99%.

When we present the findings of this hypothetical research trial to healthcare workers and the public, the directors of this research do not think people will be very impressed with a mere 1% reduction in heart attacks. Therefore, instead of using the absolute risk reduction (ARR), they present the benefit in the form of relative risk reduction (RRR). The RRR is the derivative of ARR in which the difference in disease outcomes in the two groups are expressed as a ratio. Hence, using an RRR, the directors can state that STATIN treatment reduces the incidence of heart disease by 50% because 1 is 50% of 2.

Let’s take a real life example from the medical literature. The first one is the JUPITER trial [16], in which rosuvastatin (Crestor) or placebo was given to 17,802 healthy people with elevated C-reactive protein, but with no prior history of CHD or elevated cholesterol levels. The primary outcome was the occurrence of a a major cardiovascular event, defined as nonfatal heart attack, nonfatal stroke, hospitalization for unstable angina (chest pain), arterial revascularization or death from cardiovascular causes. The trial was stopped after a median follow-up of 1.9 years. The number of subjects who experienced an event (referred to as and endpoint) was 251 (2.8%) in the control group and 142 (1.6%) in the rosuvastatin group. The difference in endpoint rate of 2.8% vs 1.6% yields an ARR of 1.2 percentage points and an NNT of 83 (83 people need to be treated to stop one heart attack or stroke). The benefit with regards to the number of fatal and nonfatal heart attacks was even smaller. There were only 68 (0.76%) vs 31 (0.35%) events, respectively, resulting in, an ARR of 0.41 percentage points and an NNT of 244. This means that regarding fatal and nonfatal CHD, less than one-half of 1% of the treated population (0.41%) benefited from rosuvastatin treatment, and 244 people needed to be treated to prevent a single fatal or nonfatal heart attack. Despite this meager effect, in the media the benefit was stated as “more than 50% avoided a fatal heart attack” because 0.41 is 54% of 0.76.

So the public and healthcare workers were told that a 54% reduction of heart attacks occurred when taking rosuvastatin (Crestor) when the actual effect in the treated population was a reduction of less than 1 percentage point. Additionally, the ARR of 0.41 percentage points was the combination of fatal and nonfatal heart attacks. There was little attention paid to the fact that more people had died from a heart attack in the treatment group. Even experienced researchers may have overlooked this finding because the figures were not explicitly stated in the report. One needs to subtract the number of nonfatal CHD from the number of ‘any MI’ to see that there were 11 fatal heart attacks in the treatment group, but only six in the control group.

Despite the miniscule effects of rosuvastatin reported in the publication, the JUPITER findings were presented as very impressive. In fact drug representatives showed up in my office jumping up and down, they were so excited by this news. In an article in Forbes Magazine, John Kastelein, a co-author of the study, proclaimed: “It’s spectacular . . . We finally have strong data” that a statin prevents a first heart attack. This triumphant declaration of victory in the war on cholesterol convinced a US FDA advisory panel to recommend Crestor treatment for people with elevated C-reactive protein levels and normal levels of cholesterol. Now you know why so many people claim C-reactive protein should be measured.

According to a table in the JUPITER report there was no difference between the numbers of serious adverse effects between the two groups. However, in the rosuvastatin group there were 270 new cases of diabetes, but only 216 in the control group (3% vs 2.4%; p < 0.01). Unlike beneficial effects, which the authors amplified in the magnitude of its appearance using RRR, the significant effect of new onset diabetes by Crestor treatment was expressed only in the ARR form.

If you were to give an objective assessment of the JUPITER findings, they should be conveyed to potential patients by saying: ‘Your chance to avoid a nonfatal heart attack during the next 2 years is about 97% without treatment, but you can increase that to about 98% by taking a Crestor every day. However, you WILL NOT prolong your life, and there is a risk you may develop or worsen your diabetes, not to mention other serious side effects like muscle aches, body aches, fatigue, and liver damage that occurs 5-6% of the time.

Let’s look at a second example. The second trial we have focused on is the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTLLA) [17]. The reason to look at this study is that it is promoted in advertisements to the public and medical professionals as representative of the robust effects of CHD risk reduction with statin treatment in primary prevention.

This trial included 10,305 people with high blood pressure (hypertension). In addition, all of them had at least three of the following risk factors: Type 2 diabetes, left ventricular hypertrophy, peripheral arterial disease, previous stroke or transient ischemic attack (TIA), or smoking. Half of them received 10 mg atorvastatin, half of them a placebo and the primary endpoint was nonfatal and fatal CHD.

The trial was planned to continue for 5 years, but the authors found the preliminary findings so impressive that the study was terminated at 3.3 years. The reason was that at that time “cholesterol lowering with atorvastatin 10 mg conferred a 36% reduction in fatal CHD and nonfatal MI compared with placebo.”

However, the actual benefit was unimpressive. In the placebo group, 3% suffered a heart attack vs 1.9% in the atorvastatin group. Thus, the ARR was only 1.1 percentage points, which is 36% of 3. Moreover, there was no significant benefit in subgroups of patients at high risk of CHD, including those with diabetes, left-ventricular hypertrophy and previous vascular disease or for patients aged 60 years or younger, for those without renal dysfunction and for individuals with metabolic syndrome. For women there were NO BENEFIT AT ALL. Indeed, there was a trend for worse, albeit non-significant, effects. Finally, there was no effect on either cardiovascular or non-cardiovascular death. Why was ASCOT stopped prematurely after 3.3 years when there was a notable absence of benefit in most measures. Because the primary basis of the premature termination was ‘the impressive 36% reduction of fatal CHD and nonfatal MI’, which also became the focal point of advertisements. See their advertisement below.

It is important to illustrate how the RRR of 36% was derived. Dr. David Diamond presented the illustration below when he combined all this data together in the figure below.

The * implies group differences that were statistically significant based on relative risk reduction [17].

The figure above illustrates the following points:The first column reveals that 97%, virtually all of the placebo-treated patients, did not have a nonfatal MI or die of CHD.The next series of categories illustrates the almost complete absence of other major coronary events in placebo-treated subjects. The asterisks in the figure above represent statistically significant effects which are based on the miniscule differences in the rate of events between the drug and placebo-treated groups. you can clearly see, the difference in outcomes with drug treatment is only about one percentage point for all measures.

What is the take home message from this article?

If you have not had a previous heart attack or stroke, your risk of having one if your C-RP is elevated is about 3% over the next five years. Taking a cholesterol drug only decreases that risk by about 1%.  Yet, there is a 5% chance you will have severe side effects to this medication including muscle aching, fatigue, erectile dysfunction, lowered testosterone, neuropathy, dementia and hemorrhagic stroke [17, 18, 19, 20, 21, 22].

It is tempting to be cynical and pessimistic about the future. And, there is a great appeal to the the individual to take a pill that offers the promise of a longer life, living heart attack free. The reality, however, is that STATINs actually produce only a very small beneficial effect on CVD outcomes, and their adverse effects are far more substantial than is generally known. Yet, if the pharmaceutical industry continues to expand its control over medical education, research and the media, then in the next few years, adults, as well as children with elevated cholesterol levels [23], will be on a statin.

Click below to read further about what I recommend in place of STATINs, the true side effects you can expect from a STATIN and the actual benefit of STATIN use after a heart attack or stroke . . .

Click HERE to read Part II: Using a STATIN after heart disease and the SIDE EFFCTS

References:

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