Review reveals statins only extend life by 3 or 4 days. Closer analysis finds they may actually shorten life.

This study was published in the BMJ Open 2015 Sep 24;5(9):e007118

Study title and authors:
The effect of statins on average survival in randomised trials, an analysis of end point postponement.

Kristensen ML, Christensen PM, Hallas J.
Department of Clinical Pharmacology, University of Southern Denmark, Odense, Denmark.

This can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/26408281

The objective of the study was to estimate the average postponement of death by statin users in statin trials. The study included an analysis of 11 trials that were defined by being randomised, having at least 1000 patients included, comparing a statin with no treatment or placebo, having at least two years of follow-up. Six of the studies were for primary prevention and five for secondary prevention with a follow-up between 2.0 and 6.1 years.

The analysis found:
(a) In primary prevention trials statin users lived an extra 3.2 days.
(b) in secondary prevention trials statin users lived an extra 4.1 days.

So the results show that - with the massive expense of buying the drugs, with the plethora of debilitating side effects, such as diabetes, muscle damage, heart failure, suicide, homicide, accidental death, cognitive impairment, Alzheimer's, dementia, birth defects, cancer, cataract, erectile dysfunction, fatigue, liver damage, lung disease, memory loss, pancreatitis, peripheral neuropathy, rhabdomyolysis, and many, many more - with all these toxic side effects statins may (supposedly) increase your life by only three of four days.

However, do they even prolong life by this paltry amount?

Clinical trials with statins are performed in highly selected populations. Most statin trials have exclusion criteria that screens out a significant percentage of people because of health and toxicity concerns. This has the effect of making the statin drugs look better than they actually are.

In the real world, few people are discouraged from using statins by the medical profession, so many people who would not be allowed in the clinical trials are taking statin drugs. This is why clinical trials show that side effects are suffered by about 5% of participants, yet in reality the figure can be anything from a fifth to over two thirds (or even more) of all statin users. 

The begs the question, that if more people suffer toxic side effects than the clinical trials portray, then do people who are taking statin drugs also have a shorter life?

In trying to determine an answer to this question it may be helpful to look at the exclusion criteria in the eleven trials in this study.

The eleven trials were:
ALLHAT
ASCOT
CARDS
JUPITER
MEGA
WOSCOPS
4S
GISSI-HF
GISSI-P
LIPID
CORONA

(1) Exclusion criteria for the ALLHAT trial:
(i) People intolerant of statins: It's anyone's guess what this number is.
(ii) Those with liver or kidney disease.
(iii) Other contraindications for statin therapy: This may include hypothyroidism; pregnancy; lactation; excess alcohol intake; use of drugs such as: amiodarone, verapamil, diltiazem, erythromycin, clarithromycin, ciclosporin, itraconazole, ketoconazole, HIV protease inhibitors, nefazodone and ciclosporin; consumption of grapefruit or grapefruit juice; use of warfarin; patients at risk of haemorrhagic stroke.
(iv) Secondary cause of hyperlipidemia: This may include patients with diabetes; hypothyroidism; nephrotic syndrome; renal failure; use of drugs such as; adrenal steroids, isotretinoin, thiazides, anticonvulsants, oral contraceptives and alcohol; those who have obstructive liver disease, hepatitis, gaucher disease, von Gierke disease, acute intermittent porphyria, anorexia nervosa, systemic lupus erythematosus; the obese and those who smoke cigarettes. 

(2) Exclusion criteria for the ASCOT trial:
(i) Patients who had had a previous heart attack.
(ii) Those with angina.
(iii) A stroke within the previous 3 months.
(iv) Fasting triglycerides higher than 4·5 mmol/L.
(v) Heart failure.
(vi) Uncontrolled arrhythmias.
(vii) Anyone with a haematological (blood) or biochemical (chemical substances and vital processes) abnormality. 

(3) Exclusion criteria for CARDS:
(i) Any past history of myocardial infarction, angina, coronary vascular surgery, cerebrovascular accident, or severe peripheral vascular disease.
(ii) Abnormal kidneys.
(iii) High blood sugar.
(iv) Those who take their drugs less than 80% of the time.

(4) The JUPITER trial:
(i) 89,890 patients were screened for the study; (only 17,802 patients were finally entered into the trial.)
(ii) 37,611 patients were excluded because their LDLcholesterol was more than 130 mg/dL.
(iii) 25,993 because their C-reactive protein was less than 2.0 mg/L.
(iv) 957 patients for diabetes.
(v) 349 patients for hypothyroidism.
(vi) 305 patients for liver disease.
(vii) Many others for hypothyroidism, hypertriglyceridemia, concurrent use of hormone replacement therapy, or cancer in the last 5 years before enrolment
(viii) Additionally, 3,948 patients withdrew consent.
(ix) An additional 1,521 patients were excluded later after a 4-week placebo run-in for poor compliance.
(x) Despite all the scrutiny in choosing patients for the JUPITER trial, at the time of study termination, only 75% of study participants were still taking their study medication.

(5) The MEGA trial:
(i) 15,210 patients entered a 4-week run in phase, but 7,201 (48%) were excluded and only 8,009 finally participated in the trial.
(ii) Reasons for exclusion included: lack of effect on cholesterol, kidney and liver disease: and because "the patient had little probability of complying with the treatment".

(6) Exclusion Criteria for the WOSCOPS trial:
(i) History of treated heart attack.
(ii) Hospitalization for angina within prior 12 months.
(iii) Electrocardiogram abnormalities,.
(iv) Arrhythmia.
(v) Frequent premature ventricular contractions.
(vi) More than 2nd degree atrioventricular Block.
(vii) High blood pressure.
(viii) History of rheumatic heart disease.
(ix) Congenital heart disease.
(x) Cor pulmonale, chronic bronchitis, emphysema, or kyphoscoliosis associated with EKG changes.
(xi) Cardiomegaly, congestive cardiac failure, or significant valvular heart disease.
(xii) Other suspected serious physical illness.
(xiii) Psychiatric illness.
(xiv) Laboratory exclusions.

(7) 4S trial exclusion criteria:
(i) Premenopausal women of childbearing potential.
(ii) Secondary hypercholesterolaemia (see ALLHAT (iv)).
(iii) Unstable or Prinzmetal angina, tendon xanthomata.
(iv) Planned coronary artery surgery or angioplasty.
(v) Heart attack during the preceding six months.
(vi) Antiarrhythmic therapy.
(vii) Congestive heart failure requiring treatment.
(viii) Persistent atrial fibrillation.
(ix) Cardiomegaly.
(x) Haemodynamically important valvular heart disease.
(xi) Stroke.
(xii) Impaired liver function.
(xiii) Partial ileal bypass.
(xiv) History of drug or alcohol abuse.
(xv) Poor mental function.
(xvi) Other serious disease.
(xvii) Intolerant of statins.

(8) The GISSI-HF exclusion criteria:
(i) Heart attack, unstable angina or revascularization procedure within 1 month.
(ii) Planned cardiac surgery, expected to be performed within 3 months.
(iii) Congenital or primary valvular etiology.
(iv) Intolerant of statins.
(v) Liver disease.
(vi) Pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception.
(vii) Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol.
(viii) Presence of any non-cardiac disease (e.g. cancer) that is likely to significantly shorten life expectancy.
(ix) Kidney abnormalities.

(9) GISSI-P trial was an open trial on secondary coronary heart disease prevention: 4,271 recent acute heart attack patients with total blood cholesterol more than 200 mg/dl (5.1 mmol/L) were randomised to pravastatin 20 mg daily or no treatment.

(10) Exclusion criteria for the LIPID trial:
(i) Clinically significant medical or surgical event within three months before study entry.
(ii) Heart failure.
(iii) Kidney or liver disease.

(11) CORONA exclusion criteria.
(i) Prior statin-induced myopathy or hypersensitivity.
(ii) Decompensated chronic heart failure or need for inotropic support.
(iii) Heart attack within past 6 months.
(iv) Unstable angina or stroke within past 3 months.
(v) Coronary artery bypass graft (or similar), pacemaker within past 3 months or plan to implant.
(vi) Prior heart transplant.
(vii) Significant uncorrected primary valvular heart disease.
(viii) Malfunctioning prosthetic valve.
(ix) Hypertrophic cardiomyopathy.
(x) Acute endomyocarditis/myocarditis.
(xi) Pericardial disease.
(xii) Systemic disease (eg, amyloidosis).
(xiii) Liver disease.
(xiv) Chronic muscle disease.
(xv) Prior cyclosporine.
(xvi) Life-limiting condition (cancer etc).
(xvii) Suspected poor compliance to protocol.

This investigation of the exclusion criteria and run-in phases of statin trials reveals the reasons that the large significant percentage of people are excluded from entering the statin studies.
(a) Most trials weed out people who are intolerant of statins.
(b) Subjects with liver or kidney problems are normally excluded.
(c) Women of child bearing age are routinely not allowed.
(d) Patients are often barred who have had surgical procedures.
(e) Most studies don't allow patients with a wide range of heart conditions.
(f) People who use drugs or alcohol are not included in statin studies.
(g) Up to 80% of screened potential subjects are rejected from the trials.
(h) Patients with various concomitant illness are invariably excluded from the trials.
(i) Patients taking a wide range of pharmaceutical drugs are not allowed into the studies.
(j) Poor mental function patients are screened out.
(k) Many of the trials weed out potential subjects who they suspect will have poor compliance in taking the statin drugs.

 

A couple of the studies have a 'run-in' phase where potential subjects are weeded out through various criteria. These trials have amounted to about a 50 to 80% exclusion rate before the trial begins. Nearly all the trials have a whole plethora of exclusion criteria and although it is very difficult to quantify how many people have been excluded, it may be argued that the 50 to 80% exclusion rate may be broadly similar.

 

How can we answer the question "do people taking statins have a shorter life?" 

 

The above eleven statin trials included 92,135 subjects. If we take the lower exclusion rate of 50%, then potentially about another 46,000 statin intolerant or statin incompatible people could have been included in the trials.

 

This would dramatically reduce the already paltry "three or four days statins add to life".

 

How can an accurate revised death rate figure can be calculated? I don't know if it's possible. But with data from an extra 46,000 statin intolerant people to be crunched there would be an exponential rise in side effects with a concomitant rise in deaths.

 

So, even if the actual exclusion rate figure is less than the estimated 50% exclusion rate figure, I suspect that this closer analysis of clinical trials reveals that statins may actually shorten life in the real world.