Statins: we need an independent review
BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i4992 (Published 15 September 2016) Cite this as: BMJ 2016;354:i4992Documents relating to a complaint about The BMJ made to COPE - updated in November 2016
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Dear Editor
TITLE: Getting the data on statins: what do European regulators hold and know? An update
The BMJ’s campaign for an independent review of the statins trial data is ongoing [1] and researchers continue to seek clarity on the benefits and harms of statins in primary prevention. Access to regulatory documents is likely to answer important clinical questions regarding these widely prescribed public health drugs. In the first phase of our research, we determined that EMA did not license statins (only combination formulas). Therefore, we approached 32 national regulators within the European Union (EU) and the European Economic Area (EEA). Our aim was to obtain a unifying overview of the licensing details of statins and ultimately map regulatory data holdings for these public health drugs.
We have now published the results of this first phase of our research.[2] We discovered a fragmented regulatory structure which proved to be complex and time consuming. Twenty-two countries replied to our requests in full. Seven countries did not respond satisfactorily and three did not respond at all. Notably, many drug regulators that had licensed statins for primary prevention claimed that they did not have any trial data in their possession. At a time when the controversy about statins in primary prevention continues unabated, drug regulators remain silent.
Our work highlights the need for all regulatory agencies to follow the lead of EMA, and more recently Health Canada, in allowing independent, third party access to regulatory trial data.[3] The issue of whether drug regulators are fulfilling their mission to inform and protect the public remains pressing and continues to be the subject of ongoing research.
[1] The BMJ. Statins - a call for transparent data. 2019. https://www.bmj.com/campaign/statins-open-data Accessed Feb 28, 2020
[2] Jefferson, T, Demasi M, Doshi P. Statins for primary prevention: what is the regulator's role? BMJ Evidence Based Medicine. 2020 0:0 http://dx.doi.org/10.1136/bmjebm-2019-111321
[2] RIAT Support Center. Regulatory Resources.
2020. https://restoringtrials.org/regulatory-resources/ Accessed Feb 28, 2020
Competing interests: MD has written about statins in scientific and lay articles and her work on this project is funded by the Nordic Cochrane Centre. TJ’s full disclosure is online (https://restoringtrials.org/competing-interests-tom-jefferson/). PD was the recipient of an award from the American Association of Colleges of Pharmacy for studying harms information on statin prescribing information (2015). He is also an editor at The BMJ and unpaid member of the Reagan-Udall Foundation for the FDA, which focuses on drug safety.
Competing interests: No competing interests
Godlee called for an independent review of the statins trial data with special attention paid to the vexed questions about the benefits and harms in primary prevention, i.e. in people at possible risk of cardiovascular disease but with no overt signs or symptoms. This is especially true for low grade musculoskeletal and joint symptoms which some observational studies report as common, and is at odds with reviews of controlled clinical trials.
As a preliminary step to research that addresses this question of the possible harms of statins, we are trying to clarify which governments across Europe have evaluated and currently hold the trial evidence on which the seven statins were approved? The European Medicines Agency did not centrally authorise any of the statins; single nations did.
We have begun this work by sending the following template letter to 32 national regulators across Europe, in the hope of achieving a single unifying overview of the regulatory data holdings for these public health drugs.
12 April 2019
To: [Regulatory Agency of Country X]
Re: Clinical Trial Evidence of Statins
We are writing to you regarding seven statin drugs:
• Atorvastatin (Lipitor, Pfizer)
• Fluvastatin (Lescol, Novartis)
• Lovastatin (Mevacor, Sandoz/Merck
• Simvastatin (Zocor, Merck)
• Pitavastatin (Livazo, Recordati/Kowa Co)
• Pravastatin (Pravachol, Bristol Meyers Squibb)
• Rosuvastatin (Crestor, AstraZeneca)
As a National Competent Authority (NCA) of the Member States of the European Union (EU) responsible for granting a marketing licence to various drugs, we would like you to answer the following questions for the purpose of enabling research to be carried out at the Nordic Cochrane Centre on the harms of statins.
These questions apply to each of the seven statin drugs mentioned above and generic brands in any dosage or format but not in combination with other drugs (e.g. fibrates);
1. Are any of the seven statins authorised in [Country X]? (yes/no for each statin)
2. If yes, what year was each statin authorised?
3. Was each statin first authorised on the basis of [Country X]'s assessment of a marketing authorisation application (MAA)? (yes/no)
4. If Q3 = yes. Does Country X still hold the clinical trial evidence (including clinical study reports) in its archives? (yes/no)
5. If Q3 = no. Which country evaluated the MAA and granted a license that was recognized by [Country X] (for example, on the basis of the mutual recognition or decentralised or national authorisation procedures)?
6. If [Country X] authorised the statin please refer us (via a weblink or URL) to the healthcare professional prescribing information for each statin, in English if possible.
To facilitate your answers please fill in this table (also attached for your convenience).
[Blank table omitted because of formatting difficulties.]
We look forward to your response. Please respond to: tj@cochrane.dk
Yours sincerely,
Tom Jefferson MD MSc MRCGP FFPHM
Nordic Cochrane Centre
Rigshospitalet, Dept 7811
Maryanne Demasi PhD
Nordic Cochrane Centre
Rigshospitalet, Dept 7811
Peter Doshi PhD
University of Maryland School of Pharmacy/
Baltimore, MD
U.S.A.
Competing interests: TJ is in receipt of funding from the University of Oxford for this work. A complete disclosure is at https://restoringtrials.org/competing-interests-tom-jefferson/. PD is an associate editor at The BMJ and served on The BMJ’s 2014-15 statins advisory panel. He has conducted research on the possible harms of statins that was financially supported by a New Investigator Award from the American Association of Colleges of Pharmacy. MD: no conflicts of interest.
Dr Leonard Williams' suggestion of a small-scale trial specifically to examine muscle side-effects is sensible, but it must last long enough. Whether one calls muscle pain myalgia, myopathy or myolysis it may not manifest itself immediately. In my own case it also varied between the different statins. Simvastatin produced effects after about 3 months (while severe tenosynovitis in tibialis anterior may sound odd, the only published cases I found when I developed this were statin-related.) Severe polymyalgic symptoms occurred on atorvastatin after two days. A more insidious myopathy on rosuvastatin took nearly 6 months to appear (associated with a seven-fold rise in creatine kinase). While I am no more than a case report it would be a pity to run a trial of such importance and risk a negative result because it was terminated too quickly.
Competing interests: I am a member of THINCS
I congratulate Shah Ebrahim and George Davey Smith for changing their minds in response to new information. I look forward to having the opportunity of doing the same when the anonymised individual patient data (IPD) and clinical study reports (CSRs) from the statin trials have been made available for independent review. This is what others have called for[1] and what I have asked the Chief Medical Officer to make happen.[2]
I agree that your Cochrane review was independent of industry and of the trialists, but you didn’t have access to these raw data. Nor, so far as I am aware, have you sought access or called for the data to be made available. You relied on the CTT collaborators analysis, which itself had only half of the IPD from the trials: the half relating to benefits of statins, not their harms. Via Twitter you have said that the Cochrane review of statins is no different in this to many other systematic reviews: why pick on statins?[3] Because they are one of the most widely prescribed class of drugs in the western world; because there is new guidance in the US and the UK proposing that their use should be extended to large numbers of healthy people;[4] [5] because this new guidance has created international controversy about the true balance of benefits and harms in people at low risk of heart disease; because this controversy has added to existing widespread concerns about the side effects of statins and is fuelling public confusion, including among people at higher risk of heart disease and stroke who stand to benefit most from taking statins;[6] and because, in my experience, when the IPD, CSRs and other regulatory documents are thoroughly scrutinised by fresh expert eyes, new and useful information emerges that can better guide patients and doctors in their decisions, as well as informing future research.[7]
For the moment I acknowledge that I am instinctively sceptical about the wisdom of medicating large numbers of healthy people, especially when alternatives to drug treatment exist.[8] I can think of no better outcome of this exchange than that you will put yourselves forward as one of the groups willing to review the anonymised IPD and other materials once these are made available.
1. Krumholz H. Statins evidence: when answers also raise questions. BMJ 2016;354:i4963. http://www.bmj.com/content/354/bmj.i4963
2. Hawkes N. BMJ editor asks chief medical officer to set up inquiry into statin risks and benefits. BMJ 2016;354:i5046. http://www.bmj.com/content/354/bmj.i5046
3. @fgodlee @cochranecollab nor do huge number of other reviews you with much less data you don't quibble with (and publish sometimes)
Original Tweet: https://twitter.com/mendel_random/status/776785709441187840
4. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. Clinical guideline [CG181]. NICE guidance 2014. https://www.nice.org.uk/guidance/cg181
5. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25_PA):2889-2934. doi:10.1016/j.jacc.2013.11.002. http://content.onlinejacc.org/article.aspx?articleid=1879710
6. Matthews A, Herrett E, Gasparrini A, Van Staa T, Goldacre B, Smeeth L, et al. Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data. BMJ 2016;353:i3283. http://www.bmj.com/content/353/bmj.i3283
7. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545. http://www.bmj.com/content/348/bmj.g2545
8. Tong TYN, Wareham NJ, Khaw K-T, Imamura F, ForouhiNG. Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study. BMC Medicine 2016;14:135. DOI: 10.1186/s12916-016-0677-4. http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0677-4
Competing interests: I am the Editor in Chief of The BMJ and responsible for all that it contains. The BMJ campaigns for access to the data from clinical trials and against overdiagnosis and overtreatment, through its Open Data and Too Much Medicine campaigns.
For clinicians whose armamentarium was confined to clofibrate, Niacinamide and associated flushing, resins with attendant dyspepsia, statins were a welcome addition. Gemfibrosil and fenofibrate were other options for hyperlipoproteinemias particularly with elevated triglycerides. Statins have seen ups and downs - welcomed initially in secondary prevention of atherosclerotic cardiovascular disease. When the indication extended to low risk patients, almost amounting to a panacea then, feelings were expressed as regards the correctness and soundness of the recommendations made. The crowning glory was the pleiotropic effects noticed and particularly the benefit that accrued in high dose in acute coronary syndromes.
In India, with a significant number of patients with not very high levels of LDL (as reported in the west), the element of doubt lessened with the recommendation that statins are to be used not for hypolipidemic action alone, but for reducing the cardiovascular risk which was the main concern and target. A balanced view (1) has been provided on non-cardiovascular effects associated with statins; however, there are a few patients with muscle related side effects that are disturbing and sometimes intolerable. One case of rhabdomyolysis with statins experienced can deter a clinician for a substantial period of time. However, by and large, presently Indian physicians use statins 10 mg, 20 mg in practice extensively, and 40 mg as high dose statins, the vast load of diabetic patients notwithstanding. However, the question of independent review (2) raised needs to be considered with an open mind.
The practice of Medicine is a steady flow and a continuum; undoubtedly unending "skepticism " may contribute to deprivation of drugs in some, yet going by the nature and substance of the objections raised (by a "minority " ), it would be prudent to draw from an independent review that takes into account substantial RCTs and (not just) observational studies. It is on generation/conclusion from such data that the ultimate word can be written and facts endorsed, certified with finality.
References
1 Desai C S. Non cardiovascular effects associated with statins. BMJ 2014 ;349:g 3743.
2 Godlee F. Statins: we need an independent review. BMJ 2016;354:i 4992.
The responder has been President of Indian Society of Hypertension (ISH) , Indian Society for Atherosclerosis Research (ISAR) and Geriatric Society of India (GSI).
Competing interests: No competing interests
An important problem is the unanswered question of the severity of limb/joint pains in patients on statins.
This could be easily addressed in a small controlled trial. Patients contemplating the use of statins for primary prevention could be entered into a randomised controlled trial of statin versus placebo for a short introductory period. Patients would record symptoms in a standardised fashion and allowed to discontinue therapy at their own choice. Comparison of the two groups would give a clear answer about the amount and severity of pains caused by statins. The patients should then be informed about whether they had been taking statin or a placebo in order to inform their choice on further therapy
Competing interests: No competing interests
Statins is one of the commonly prescribed medication especially when managing patients with chronic non-communicable diseases such as cardiovascular diseases (CV), and CV risky diseases like diabetes type 2 and hypertension. This is all because of huge data that support the use statin to minimize the cardiovascular fatal events which were pushed by many significant studies. Scandinavian (4S) and American Air Force/Texas Coronary Artery Prevention study ( AFCAPS/TexCAPS) were among the prominent among them.
Although, there are increasing in the amount of drawbacks from statin use. Starting from myalgia, myopathy and increase liver enzymes. As well as, patients became more relying on medication a lone to control serum cholesterol level, but not in combination with healthy lifestyle changes such as diet and exercise. In addition, the high cost of statin that has make a big burden on the patients' treatment cost as well as health authorities and governments.
Consequently, I believe, statin prescription will need to be re-evaluate according to patient prevention stages whether they are primary, secondary or tertiary prevention.
Statin has a big role in cardiovascular tertiary prevention so that there prescription is an essential for those who survive the ischemic cardiac incident.
On the other hand, statin use in secondary prevention is it in the place for review. In this stage the prescription of statin need to be narrowed. The statin prescription may be recommended when there were high risk for cardiovascular (CV) fatal or near fatal cardiac event. Such as diabetes ,hypertension diseases with poorly controlled dyslipidemia with diet and exercise alone especially when there are renal or vascular complications. However, when there are well controlled cholesterol level by diet and exercise in patients with controlled CV risk diseases the use of statin could be debatable.
Regarding primary prevention, I do not believe there is a role for statin at all. Diet and exercise are the core for prevention.
In summary, so many steps need to be take to have clear stain usage protocol by more of independent double blind research to verify the evidence.
Competing interests: No competing interests
Firstly, the basic question of statin intervention needs to be addressed. The Cholesterol - CV mortality hypothesis has been repeatedly questioned in various research articles, and at various fora, and has not elicited an answer from researchers supported by pharmaceutical interests. Cholesterol has not been found to be a causal factor in CV mortality in any study with any degree of certainty. Endothelial damage with consequent narrowing of the arteries has been proved to be the cause of atherosclerosis. Rather than address the causal factor for endothelial damage, the insistence of statin promoting research that lowering of cholesterol levels by inhibiting the production of HMG CoA reductase is the need of the hour in reducing CV mortality is unwarranted.
That the intake of statins to inhibit HMG CoA reductase interferes with the need for cholesterol for various other cellular functions, as well as the effects of non-availability of cholesterol for brain and neurological related functions, has not been recognized by the researchers of this study.
The issue of myopathy and rhabdomyolysis in particular has been minimally addressed. Time and again, it has been proved that even small doses of statins result in myopathy in varying degrees of severity. Depletion of CoQ10 is another issue that has not been addressed at all.
The issue of increase in the risk of strokes in patients is another cause for concern. Liver disease and pancreatitis have been mentioned in passing but have not been dealt with any great detail.
The issue here is not one of the efficacy of statins on the production of cholesterol by inhibiting HMG CoA, but a question of the necessity for controlling cholesterol except in cases of Familial Hypercholesterolemia.
Competing interests: No competing interests
The need for an independent review is pressing. The latest paper in The Lancet appears to be a rehash of previous results but it has been impossible to get to the truth because of the failure of Collins et al to allow access to the raw data. Hence it is now claimed that side-effects are low when previously it was alleged that the data didn’t exist.
However, what really needs review is the question of whether cholesterol falls are an epiphenomenon and also what is the real reduction in cardiovascular risk. Thus we need clear data on absolute not relative risk and clear data on life expectancy. If, as other valid studies have suggested, the absolute risk reduction is less than 5%, and the prolongation of life is a matter of days or weeks then the whole issue of side-effects becomes irrelevant.
Competing interests: I am a member of THINCS
We agree - an Independent REVIEW & QUANTIFICATION of the true benefits and risks of Statins, PCSK9-inhibitors and Diets - including LowCarb-KETO and Vegan Diets – is long overdue!
Saturated fats and LDL-cholesterol are two of the major contributing factors responsible for Inflammation and Heart Disease, angina and subsequent myocardial infarction and death, as established by the first author beginning in the mid-1990s [1-4]. Anyone who suggests otherwise is either too unfamiliar with the “Inflammation and Heart Disease” and “Angina” Theories or simply does not understand them (https://bjsm.bmj.com/content/51/15/1111.responses) [5]. While it is important to recognize what negative side effects these drugs and diets might have on people; we cannot fully appreciate the risks and benefits until we understand what we are actually treating.
The mere measurement of lipids and markers of inflammation (CRP, IL-6, et cetera) through serum testing, correlate poorly with the extent and severity of coronary artery disease (CAD), and measurement of their change only moderately correlate with changes in CAD [6].
The reason for the differences between blood testing and measurement of CAD outcomes [6-8] should be obvious [1,3] and has been explained multiple times [6, 9-17]. Coronary artery disease is an inflammatory process involving the walls, and subsequent function, of the coronary arteries, and it is at this tissue level where the interaction of these inflammatory mediators results in CAD. Consequently, measurement of treatment – drugs or diet - purporting a beneficial reduction in CAD, cannot rely on serum blood testing to demonstrate such benefit.
It is also true there are potential risks associated with the use of lipid lowering and dietary regimens [17-22], and it is at the tissue level again, where the risk or harm of these drugs and diets are best understood. Problems including inter alia myalgias and CoQ10 deficiencies following statin medications represent concerns long recognized, but not addressed by BigPharma (https://www.bmj.com/content/368/bmj.m579/rr-0) [23].
The controversy over the risk benefit ratio of these lipid lowering drugs and dietary regimens represents a problem, not only because of information not being released by BigPharma, but because of information not being released by BigFood and purported dietary pundits. If we are to address these concerns we must call for the independent review and measurement of the true risks and benefits associated with both lipid lowering drugs and popular dietary regimens – close is now longer good enough (https://link.springer.com/article/10.1007/s00259-019-04668-y )[24].
References:
1. Fleming RM. Chapter 29. Atherosclerosis: Understanding the relationship between coronary artery disease and stenosis flow reserve. Textbook of Angiology. John C. Chang Editor, Springer-Verlag, New York, NY. 1999. pp. 381-387.
2. Fleming RM. Chapter 30. Cholesterol, Triglycerides and the treatment of hyperlipidemias. Textbook of Angiology. John C. Chang Editor, Springer-Verlag, New York, NY. 1999, pp. 388-396.
3. Fleming RM. Chapter 64. The Pathogenesis of Vascular Disease. Textbook of Angiology. John C. Chang Editor, Springer-Verlag New York, NY. 1999, pp. 787-798.
4. 20/20 Segment on Heart Disease and Inflammation. https://www.youtube.com/watch?v=Hvb_Ced7KyA&t=22s
5. Fleming RM, Fleming MR, Chaudhuri TK. The author of the Inflammation and Heart Disease Theory Cautions – Cholesterol and Saturated Fat are an Integral part of the Inflammatory process we call Coronary Artery Disease. Re: Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions. 23 February 2020 for Br J Sports Med 2017;51(15):1111-1112. https://bjsm.bmj.com/content/51/15/1111.responses
6. Fleming RM, Harrington GM. What is the Relationship between Myocardial Perfusion Imaging and Coronary Artery Disease Risk Factors and Markers of Inflammation? Angiology 2008;59:16-25.
7. The Fleming Method for Tissue and Vascular Differentiation and Metabolism (FMTVDM) using same state single or sequential quantification comparisons. Patent Number 9566037. Issued 02/14/2017.
8. Fleming RM, Fleming MR, Chaudhuri TK. Replacing Cardiovascular Risk Factors with True AI and Absolute Quantifiable Measurement (FMTVDM) of Coronary Artery Disease. Inter J Res Studies Med & Health Sci. 2019;4(11):11- 13. ISSN:2456-6373.
9. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316(22):1371-1375.
10. Fleming RM., Kirkeeide RL, Smalling RW, Gould KL. Patterns in Visual Interpretation of Coronary Arteriograms as Detected by Quantitative Coronary Arteriography. J Am Coll. Cardiol. 1991;18:945- 951.
11. Fleming RM, Harrington GM. Quantitative Coronary Arteriography and its Assessment of Atherosclerosis. Part 1. Examining the Independent Variables. Angiology 1994;45(10):829-833.
12. Fleming RM, Harrington GM. Quantitative Coronary Arteriography and its Assessment of Atherosclerosis. Part 2. Calculating Stenosis Flow Reserve Directly from Percent Diameter Stenosis. Angiology 1994;45(10):835-840.
13. Fleming RM. Shortcomings of coronary angiography. Letter to the Editor. Cleve Clin J Med 2000;67:450.
14. Fleming RM. Coronary Artery Disease is More than Just Coronary Lumen Disease. Amer J Card 2001;88:599-600.
15. Fleming RM, Harrington GM. TAM-A.7 Sestamibi redistribution measurement defines ischemic coronary artery lumen disease. 56th Annual Meeting of the Health Physics Society. (American Conference of Radiological Safety) West Palm Beach, FL, USA.
16. Fleming RM, Fleming MR, Chaudhuri TK. Are we prescribing the right diets and drugs for CAD, T2D, Cancer and Obesity? Int J Nuclear Med Radioactive Subs 2019;2(2):000115.
17. Fleming RM, Fleming MR, Chaudhuri TK, Harrington GM. Cardiovascular Outcomes of Diet Counseling. Edel J Biomed Res Rev. 2019;1(1):20-29.
18. Fleming RM, Fleming MR, Chaudhuri TK. Recognizing the fundamental flaw in our dietary studies investigating the impact diets, drugs and lifestyle have on preventing or reversing CAD. J Cardiovasc Med Cardiol 2020;7(1):36-38. DOI: 10.17352/2455-2976.000109.
19. Fleming RM, Fleming MR, Chaudhuri TK. What is the role for treatment of hyperlipidemia in the primary prevention patient? J Cardiovasc Med Cardiol 2020;7(1):004-005.
20. Fleming RM, Fleming MR, Chaudhuri TK. Are statins overprescribed? J Cardiovasc Med Cardiol 2020;7(1):001.
21. Fleming RM, Fleming MR, Chaudhuri TK. How Should We Treat Hyperlipidemia in the Primary Prevention Patient? Am J Biomed Sci & Res. 2019;6(6):459-461. DOI:10.34297/AJBSR.2019.06.001082.
22. Fleming RM, Fleming MR, Chaudhuri TK. Coronary Artery Calcium (CAC) Scoring and Treatment Decision Making. J Cardiovasc Med Cardiol 2019;6(4):92-93. DOI:10.17352/2455-2976.000200.
23. Fleming RM, Fleming MR, Chaudhuri TK. The real question isn’t whether Inclisiran reduces LDL cholesterol – but whether Inclisiran reduces coronary artery disease. Re: UK deal over inclisirin. 23 February 2020. BMJ 2020;368:m579. https://www.bmj.com/content/368/bmj.m579/rr-0
24. Fleming RM, Fleming MR, Dooley WC, Chaudhuri TK. Invited Editorial. The Importance of Differentiating Between Qualitative, Semi-Quantitative and Quantitative Imaging – Close Only Counts in Horseshoes. Eur J Nucl Med Mol Imaging. DOI:10.1007/s00259-019-04668-y. Published online 17 January 2020 https://link.springer.com/article/10.1007/s00259-019-04668-y
FMTVDM is issued to first author. First author, authored the "Inflammation and Heart Disease" and "Angina" Theories. The authors have previously addressed issues with BigPharma, the need for transparency by BigPharma and the FDA/CDER.
Competing interests: FMTVDM is issued to first author. First author, authored the "Inflammation and Heart Disease" and "Angina" Theories. The authors have previously addressed issues with BigPharma, the need for transparency by BigPharma and the FDA/CDER.