According to Dr. Lisa Bardack, the personal physician of Hillary Clinton, Ms. Clinton has had 3 episodes of venous thromboses: deep vein thromboses (DVT) 1998 (in a leg) and 2009 (? site) and cerebral venous thromboses (CVT) in 2012.(1) Each time she was presumably treated with heparin or low-molecular-weight heparin and warfarin (Coumadin) according to the American College of Chest Physicians (ACCP) clinical practice guidelines for venous thromboembolism (VTE)(2) and American Heart Association/American Stroke Association (AHA/ASA) guidelines recommending anticoagulants for CVT.(3) Ms. Clinton continues to take warfarin to prevent a recurrence of venous thrombosis. ACCP and AHA/ASA guidelines call for indefinite use of anticoagulants after 2 or more episodes of venous thrombosis.
As the author of systematic medical literature reviews about the evidence-basis for using anticoagulation for CVT (3) and venous thromboembolism (VTE: DVT and / or pulmonary embolus (PE)),(4, 5) I have the perspective to quantify the risks and benefits of anticoagulants used for treatment of venous thromboses.
ACCP clinical practice guidelines for VTE (2) call for treating with heparin (unfractionated heparin or low-molecular-weight heparin, or alternatives such as Arixtra (fondaparinux) and oral anticoagulants Coumadin (warfarin) or newer anticoagulants like Pradaxa (dabigatran), ribaroxaban (Xarelto), apixaban (Eliquis), and Edoxaban (Savaysa). For treatment of CVT, heparin and warfarin are recommended by the American Heart Association/American Stroke Association (AHA/ASA).(3)
This blog will make the case for retracting those clinical practice guidelines and withdrawing Food and Drug Administration (FDA) approval for anticoagulant treatment of CVT and VTE. It will detail why these drugs in venous thrombosis patients increase the overall risk of death while adding a risk of permanent neurological disability from bleeding into the brain.
Anticoagulants for cerebral venous thrombosis (CVT)
CVT is a rare disease affecting people of all ages (mean age: < 40-years-old). Risk factors for CVT include dehydration from gastroenteritis and head trauma as in Ms. Clinton’s case. American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend that CVT patients receive full therapeutic dose intravenous heparin (unfractionated heparin or low molecular weight heparin) for about five-seven days and a vitamin K antagonist (VKA) like warfarin (Coumadin) by mouth for at least three months.(2, 3) According to news accounts of Ms. Clinton’s CVT episode in 2012, her neurologists prescribed full therapeutic dose heparin while she was in hospital. Because this was the third venous thrombosis for Ms. Clinton, her doctors have prescribed warfarin on an indefinite basis in compliance with ACCP and AHA/ASA clinical practice guidelines. According to those guidelines, the need for warfarin or alternative oral anticoagulation should be reassessed periodically, perhaps on a yearly basis.
The AHA/ASA guidelines calling for use of anticoagulation for CVT patients were based on a Cochrane systematic review of anticoagulant therapy for CVT. The Cochrane Database of Systematic Reviews is a premier medical journal of evidence-based evaluations of medical interventions. This anticoagulants for CVT review included only two small, randomized, placebo-controlled trials (number of patients, n=79).(7) The authors found a non statistically significant trend in mortality favoring anticoagulants (deaths with full-dose heparin + warfarin for three months: 2/40, deaths with placebo: 7/39; risk ratio, 0.28; 95% confidence interval [CI], 0.04–1.36, P = 0.09). One trial included in this Cochrane review,(8) conducted in the early 1980s, was terminated early and contained several major flaws. For example, a pregnant woman with CVT lost a 38-week-old fetus as a complication of heparin. However, the authors omitted this death from the tally of deaths in heparin-treated patients.
To evaluate the efficacy and safety of full-dose heparin during initial hospitalization and subsequent warfarin treatment for CVT patients, I systematically reviewed all six randomized controlled trials (i.e., including the four that were excluded from the Cochrane CVT review) and 56 observational studies published from 1990 to 2013 (n=5155).(4) In the published reports of these studies, much of the data was missing about the anticoagulation status of patients (i.e., receiving or not receiving heparin, warfarin, or other drugs, etc.) in relationship to the CVT outcomes (i.e., death, permanent disability, and major bleeding). I emailed all the corresponding authors, asking for the relevant missing data. Only 7/62 authors supplied me with data omitted from their studies. Because of the absent data in the studies, the editor of the journal Stroke published my review as an “opinion piece.”(4) Key findings were:
- In studies reported since 2000, full-dose heparin was associated with a statistically non significant increase in hospital deaths (full-dose heparin: 9.7% (192/1980) versus no full-dose heparin, thrombolysis, or warfarin in hospital: 8.8% (9/102), RR= 1.10, CI: 0.58 – 2.26, P=1.00).
- About 5% of full-dose heparin treated patients suffered major or fatal bleeding in hospital.
- Regarding oral anticoagulation for the patients surviving the initial hospitalization, the largest CVT observational study had a sub-study of patients ≥ 65-years-old. In that sub-study of patients in Ms. Clinton’s age group, the rate of major bleeding with warfarin treatment post hospitalization was 0.60%/patient-month (2 fatal bleeds/333 patient-months in 38 CVT patients).(9)
The most common cause of death in CVT patients is by massive bleeding in the brain and infarctions (death of brain tissue) due to the venous thromboses causing swelling and increased pressure in the cranium. Intuitively, it makes little sense to treat that problem with blood thinners that make brain bleeding easier. My anticoagulation for CVT review/opinion piece concluded: “The risk of harm from anticoagulants, particularly from bleeding, is considerable. Anticoagulation for CVT is not evidence-based to be effective or safe.”(4)
An editorial in Stroke by Magdy Salim, MD, PhD of the Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center in Boston, responding to my CVT review/opinion piece, stated,
“Cundiff indeed raises valid concerns and questions of clinical and therapeutic importance that are yet to be fully answered. The use of anticoagulants in patients with CVT poses a real risk: ICH (intracerebral hemorrhage). There is paucity of data about the de novo occurrence or worsening of ICH after anticoagulant treatment in a larger number of patients to obtain more robust estimation of the risk.”(10)
At the invitation of the editor of Stroke, CVT researchers wrote letters to the editor refuting my findings and conclusions.(11, 12, 13, and 14) My rebuttals were also published.(15, 16, 17, and 18) I thought I won the debate. However, this heated exchange about a complicated analysis of efficacy and safety of drug treatment for a rare disease that most doctors have never encountered began and ended with no apparent notice of other neurologists or of the medical media.
The logical referees to weigh in on this controversy concerning anticoagulants for CVT were the leaders of the AHA/ASA. The AHA/ASA owns the journal Stroke that published:
- the anticoagulation for CVT guidelines,(6)
- my opinion piece/systematic review that challenged those guidelines,(3)
- the invited editorial,(10) and
- letters to the editor favoring and opposing the conclusions of the review.(11, 12, 13, 14, 15, 16, 17 and 18)
The AHA/ASA produces many guidelines on different matters concerning diseases of the heart, brain, and blood vessels. Concerning all AHA/ASA guidelines, the website states:(19)
The AHA and ASA encourage correspondence on statements and guidelines. The AHA and ASA welcome letters sent directly to us on statements and guidelines. The letters are brought to the attention of the Writing Committee chair/co-chairs. Any input that might have an impact on recommendations for patient care or patient safety will be considered immediately. Letters are also reviewed by the AHA/ASA Manuscript Oversight Committee. If a response is warranted, one will be sent and possibly posted on americanheart.org.
In addition to having my systematic review/opinion piece on anticoagulants for CVT published in a AHA/ASA-owned journal, Stroke, I submitted my case for the retraction of the AHA/ASA anticoagulants for CVT guidelines directly to the guidelines Writing Committee chair/co-chairs and the AHA/ASA Manuscript Oversight Committee. I detailed for them how this information may well impact patient care and patient safety. Through a nurse who intermediated our correspondence, I was told that no action would be taken by the AHA/ASA. She gave no explanation why. The AHA/ASA leaders or the CVT guidelines authors did not dispute or rebut my findings publicly or privately. The AHA/ASA leaders posted nothing regarding the controversy concerning the efficacy and safety of anticoagulation for CVT on the americanheart.org website. Instead of rebutting my case for retracting the AHA/ASA CVT guidelines for anticoagulation treatment, the AHA/ASA ignored it. Consequently, the medical media had no story, and doctors not specializing in anticoagulation heard nothing about it.
It should be noted that the AHA/ASA received over $15 million in donations from corporations in FY 2013-2014,(20) including all the drug companies that produce anticoagulants for CVT.
Anticoagulants for venous thromboembolism (VTE: DVT and/or pulmonary embolism (PE))
Rigorous randomized controlled trial evidence supporting anticoagulants for VTE is entirely absent. Warfarin, heparin, and other anticoagulant drugs have been used to treat VTE since the 1940s based on anecdotal evidence and observational studies with historical controls. Coumadin (warfarin) was approved by the FDA in 1954 without randomized trial evidence of efficacy. In 1962, the Food and Drug Administration (FDA) first began requiring randomized controlled trial evidence of efficacy before approving a drug. In 2001, I wrote to the FDA presenting my evidence that anticoagulant drugs were neither effective nor safe in the treatment of VTE. The three page response from Robert Temple, MD,(21) Medical Director of the FDA and Lilia Talarico, MD, Division of Gastrointestinal and Coagulation Drug Products contained the following relevant passages:
…heparin sodium injection was first approved on June 22, 1939 for the prevention and treatment of postoperative thrombosis and embolism and re-review of the efficacy of the drug was conducted under the DES (“drug-efficacy study”_ and its implementation program following the Drug Amendments of 1962. The National Research Council of the National Academy of Sciences (NAN/NRS) concluded in 1970 that heparin was effective for the treatment and prevention of all venous and arterial thrombosis, thromboembolic disease, and the prevention and treatment of pulmonary embolism. The FDA evaluated and concurred with the NAS/NRS report…
Early clinical trials showed reduction in mortality in patients with DVT/PE treated with heparin compared to untreated placebo-treated patients (Barritt DW, Jordan SC. Lancet 1960(8)). Although the initial clinical trials of heparin were limited in size and not performed according to the current criteria and requirements of adequate and well-controlled design, they provided substantial evidence of efficacy. Over the years, numerous clinical trials have confirmed the efficacy and safety of heparin and other antithrombotic compounds for the treatment and prevention of thromboembolic events (TEE).
While Drs. Temple and Talarico mentioned “initial clinical trials,” they only referenced one randomized controlled trial to support the efficacy and safety of anticoagulants for VTE. Barritt and Jordan conducted this RCT, which was published in The Lancet in 1960.(8) I will discuss this randomized controlled trial subsequently. The National Research Council of the National Academy of Sciences review that they referenced is not publicly available. I requested it from the FDA, and the information officer directed me to file a freedom of information form to receive the report.
I systematically reviewed the evidence-basis of anticoagulants for VTE for Medscape General Medicine.(5) Based on the same data, Juliet Manyemba, MD, John Pezzullo, PhD (biostatistician), and I later authored a review published in the Cochrane Database of Systematic Reviews.(6) Cochrane archivists found four small randomized controlled trials comparing standard anticoagulation for VTE (full-dose heparin followed by warfarin or other vitamin K antagonist drugs) versus a placebo or a non steroidal anti-inflammatory drug (NSAID).
Our review writing group excluded the randomized controlled trial by Barritt and Jordan that was published in The Lancet in 1960(8) because the authors, peer-reviewers, and editor of our Cochrane review all deemed it too flawed by current standards to be included in the review. For instance, the diagnoses of pulmonary emboli (PE) were made by clinical history, physical exam, and chest x-ray alone. Modern chest imaging tests (lung scans, angiograms, CT scans, etc.) were not available to investigators in the 1950s. Anticoagulation experts didn’t learn until 1990 that a clinical suspicion of PE is confirmed by modern imaging tests to actually diagnose PE only about 25% of the time.(22) The results of that flawed trial favored anticoagulants for PE (deaths with placebos: 5/19; deaths with anticoagulants: 0/16, P = 0.049).
The results of the three remaining randomized controlled trials surprised everyone: (deaths with standard anticoagulation: 6/66, versus deaths with placebo or NSAID: 1/60, P = 0.12). The editor omitted one trial published only as an abstract reporting that 2/7 heparin and vitamin K antagonist treated patients died versus 0/5 patients given placebos.(23) We authors contacted the lead author of that trial, Dr. V.V. Kakkar, who was still practicing in London, England. He declined to supply us with further details.
Over the objections of the authors, the peer-reviewers (five out of seven of whom had undisclosed financial conflicts of interests with drug companies producing anticoagulants) and the editor insisted that we completely change our discussion and conclusion section of the review. Not doing so would have meant the editor would not have published the review. The conclusion of the editor and peer-reviewers was substituted for the conclusion of the authors in the published review:
The limited evidence from randomized controlled trials of anticoagulants versus non-steroidal anti-inflammatory drugs (NSAIDs) or placebo is inconclusive regarding the efficacy and safety of anticoagulants in VTE treatment. The use of anticoagulants is widely accepted in clinical practice, so a further randomized controlled trial comparing anticoagulants to placebo could not ethically be carried out.
Medscape General Medicine subsequently published my viewpoint article, “Evidence-based Medicine and the Cochrane Collaboration on Trial,” that exposed the bias and financial conflicts of the Cochrane Peripheral Vascular Disease Editor and peer-reviewers regarding the VTE review.(24) This viewpoint essay concluded:
Since anticoagulation researchers and FDA scientists chose not to rebut any of the data or conclusions of either review (my two published systematic reviews of anticoagulants for VTE), the media was not interested, few physicians read the reviews, and no debate ensued. Researchers continue receiving lucrative contracts from drug companies for more anticoagulant trials. The medical establishment (drug companies, doctors, hospitals) keeps making money from the diagnosis and treatment of DVT and PE with anticoagulants (estimated total cost in 2007 will be $13 billion-$48 billion in the United States(25)), and medical journals keep publishing more anticoagulation trials without proper controls, which are dutifully covered by a compliant media, while thousands of DVT and PE patients keep bleeding to death.
This viewpoint essay too was ignored by anticoagulation researchers from Cochrane and elsewhere and, consequently, the medical media.
About four years later, the Medscape Journal of Medicine published my systematic review of Cochrane anticoagulation reviews. Dr. David Tovey, incoming Editor in Chief of the Cochrane Collaboration, publicly addressed my challenges to anticoagulation guidelines, but only from his perspective as Chief Editor of Cochrane, not actually rebutting my data or conclusions:(26, 27)
Editor in Chief’s response to a review by Dr David Cundiff in The Medscape Journal of Medicine
On 6 January 2009, The Medscape Journal of Medicine published a review by Dr David Cundiff titled “A systematic review of Cochrane anticoagulation reviews.”(26) In this review Dr Cundiff described his role as author of a Cochrane Review, and his dispute over editorial control. As a consequence of this experience, he decided to retrieve all Cochrane Reviews that evaluated anticoagulation treatment in a range of different conditions. This led him to submit 57 feedback letters to different Cochrane Review Groups (CRGs). In the review Dr Cundiff describes the handling by the CRGs of the feedback as a process, and also summarises nine categories of possible methodological errors (207 total instances) and four types of biases (18 total instances) included in the reviews.
As the incoming Editor in Chief, I was asked to prepare a report on Dr Cundiff’s review, and to assess the responsiveness of the various CRGs (Cochrane Review Groups) referred to in the review in question…
I do not intend here to comment in detail about the content of the feedback, which is more properly addressed by content experts. However, what is clear is that some of Dr Cundiff’s comments were regarded as useful and informed, and led to changes in the relevant reviews. However, in the majority of cases there was simply disagreement on the interpretation of the available evidence.
As part of my research for this systematic review of Cochrane anticoagulation reviews, I documented that 13 of the editors or peer-reviewers of Cochrane anticoagulation reviews had undisclosed financial conflicts of interest with anticoagulation-producing drug companies. In addition, 33 of the authors of these anticoagulation reviews had undisclosed financial conflicts of interest. (Footnote a) Many other Cochrane anticoagulation reviewers disclosed their financial conflicts of interest.
So Dr. Tovey is right, there is simply a disagreement in interpretation of the available evidence about the efficacy and safety of anticoagulants. Do you believe the drug company funded anticoagulation researchers or do you believe the whistleblower doctor who lost his medical license for stopping anticoagulants in a man with contraindications for using those drugs.(28)
To support anticoagulation for VTE, the most recent ACCP guidelines calling for anticoagulation treatment for VTE patients(2) referenced only the previously discussed, small, highly flawed randomized controlled trial by Barritt and Jordan published in The Lancet in 1960 (n=35).(8) The ACCP VTE guidelines article said, “The first and only randomized trial that compared anticoagulant therapy with no anticoagulant therapy in patients with symptomatic DVT or PE was published in 1960 by Barritt and Jordan…” This statement is blatantly false is several ways:
- The Barritt and Jordan trial was severely flawed by today’s standards,(5)
- There were three other randomized controlled trials published in the medical literature that involved only DVT patients, all showing no benefit or even harm with anticoagulants,(23, 29, 30)
- There were two systematic reviews of anticoagulants for venous thromboembolism published in the medical literature that excluded the flawed Barritt and Jordan trial and included the other randomized trials,
- The Barritt and Jordan randomized controlled trial involved only PE patients and no DVT patients.(8) (Ms. Clinton had DVTs in 1998 and 2009 unassociated with a PE.)
The ACCP VTE guidelines article (75 pages long) and the supplement to the article (91 pages long) included 630 references. However, besides failing to reference the three randomized controlled trials of DVT patients (23, 29, 30), the ACCP VTE treatment guidelines article omitted referencing or to discussing any of my five published systematic reviews that challenged the efficacy and safety of anticoagulants for VTE.(5, 6, 27, 31, 32) Hence, the ACCP anticoagulants for VTE clinical practice guidelines seem intended to intimidate practicing physicians into compliance with the drug company funded guidelines rather than to inform them about the clinical science regarding anticoagulants for VTE.
The funding/support statement for the ACCP VTE guidelines was as follows:
The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and Sanofi – Aventis US.
These drug companies all sell anticoagulants. They also hire academic researchers:
- to perform clinical studies involving these drugs,
- to give paid lectures to doctors about them, and then
- to write the guidelines mandating the use of anticoagulants for VTE.
The result is that an estimated 1000 – 3500 U.S. residents treated for VTE bleed to death each year from the anticoagulants.(5) At least an equal number of VTE patients each year become permanently disabled by nonfatal bleeds to the brain.
For anticoagulant-producing drug companies, this is a complicated, high financial stakes area of inconvenient clinical science. For them, ignoring evidence-based challenges while generously funding hundreds of anticoagulation medicine researchers with loyalty to their funders has worked effectively. Ms. Clinton and other VTE patients have been the losers.
Anticoagulant guidelines related to the cost of diagnosis and treatment of venous thromboses
The Center for Disease Control estimates the number of people in the USA developing VTE per year at 300,000 – 900,000.(33) Another estimate is over 1 million VTE cases per year.(34) We will use 600,000 as a reasonable estimate.
Literature estimates of the costs VTE diagnosis and treatment adjusted for inflation to 2016 are the following:
- $21 billion: based on claims data from 1998 – 2004 from 30 managed care organizations(35)
- $19 billion: from a VTE cost modeling study published in 2011.(36)
- The first novel anticoagulant became FDA approved in late 2010, so the above cost studies do not take into account the additional cost of anticoagulants.
- Emergency room diagnostic studies to rule out VTE (e.g., lung scans and ultrasonography of the legs) in patients in which VTE was ruled out were not included in these estimates.
Ms. Clinton’s risk of developing another venous thrombosis
Given that Ms. Clinton’s CVT episode was apparently caused by her dehydration and concussion and that the VTE incidence in people > 65 years old is at least 260 times the incidence of CVT ( >260/100,000/year(37, 38, and 39) versus ≈1/100,000/year(40)), her risk of a recurrent venous thrombosis is primarily from VTE.
Based on my review of many published medical studies, I estimated that Ms. Clinton’s risk of a recurrent VTE from August 2015 until January 2025 is about 20%. (Footnote b) To put this risk in context, the probability of a 67-year-old woman with no previous VTE having her first VTE episode over the next 10 years would be about 4%.(37) (Footnote c) So Ms. Clinton has about five times the VTE recurrence risk that similarly aged people have of developing a first VTE episode.
Ms. Clinton’s risk of dying should she develop another DVT or a pulmonary embolus
According to a report from the U.S. Center for Disease Control on VTE,(41) about 10% – 30% of VTE patients die within three months of diagnosis. Although only about one-third of VTE cases are PE, most deaths are from PE. People who present to the physician with DVT and die within three months of VTE virtually all die of PE or of an underlying terminal disease (i.e., cancer or heart failure).
In the three randomized controlled trials of anticoagulants for DVT,(23),(29), and (30) deaths of PE in the placebo and NSAID groups were 0/60. One control patient died of an MI.(6) These randomized trials typically excluded VTE patients with expected survivals of < 3 months (the duration of the trial).
In DVT and PE patients without advanced underlying disease (e.g., cancer or heart failure), I estimate chance of dying in the first 3 months with no anticoagulants at < 1% and 1.5%, respectively. (Footnote d)
Ms. Clinton’s risk of major bleeding should she receive more anticoagulant drugs for venous thrombosis
If Ms. Clinton has another venous thrombosis episode (either CVT or VTE) in the future, the ACCP VTE treatment guidelines state the following:(2)
184.108.40.206. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B), and we suggest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B)…
In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (e.g., annually)…
“Moderate bleeding risk” is defined as having a single bleeding risk factor. The risk factors for major bleeding include age > 65 years, previous major bleeding, cancer, kidney failure, liver failure, etc.(2) From what has been reported by Ms. Clinton’s doctor, her only bleeding risk factor is age > 65 years. She has no inherited or acquired coagulopathies according to her doctor’s report.(1)Consequently, Ms. Clinton is receiving “extended oral anticoagulation” (warfarin), which will continue indefinitely.
What will be her risks of major bleeding with lifelong anticoagulants for VTE?
A good way to estimate the risk is to refer to data from a meta-analysis of all the available studies in the medical literature that relate to the question. A meta-analysis, like a systematic review, combines all the patients from all studies of the same medical condition in order to have much greater statistical power and reliability.
Related to Ms. Clinton’s long-term major bleeding risks with any future anticoagulation for VTE, one meta-analysis concerned bleeding risk in the first three months of anticoagulation treatment.(42) Another meta-analysis addressed her major bleeding risk after the first three months of anticoagulation for VTE.(43) The cumulative risk of Ms. Clinton having a major bleed with extended anticoagulation would again depend on her age at the onset of the anticoagulation and the duration of treatment. Given that she has received warfarin since December 2012 and will do so indefinitely, her chances of major, fatal, and nonfatal brain bleeding at some time before January 2025 are the following:
- major bleeding ≈ 50%, (Footnote e)
- fatal bleeding ≈ 5% (10% of major bleeds(43)), and
- nonfatal brain bleeding ≈ 6% (13% of major bleeds(43)).
In contrast to an otherwise healthy Ms. Clinton’s < 2% chance of dying of the complications of a recurrent venous thrombosis should she not receive anticoagulants for a new episode of CVT or VTE, her risk of dying or having a disabling nonfatal CNS bleed over the next 9.5 years (9 years and 6 months) should she have extended anticoagulation over that time would be in the range of 10%.
Evidence that diet may reduce the risk of venous thrombosis
If Ms. Clinton’s risk of a recurrent venous thrombosis is about 20% over the next 10 years, might a dietary change reduce that risk?
Some data collected during wartime address that question.
During the Second World War, people in Norway, Sweden, Switzerland, Germany, Finland, and Denmark had significantly reduced intake of food from animal sources. However, only Denmark showed no decrease in vascular disease mortality (including VTE mortality). In Denmark alone, there was no significant reduction in consumption of dairy fats and eggs.(44)
In Norway from 1940 to 1944, intake of meat, whole milk, cream, margarine, cheese, eggs, and fruit decreased markedly while people increased their intake of whole grain bread, potatoes, fresh vegetables, fish, cod liver oil, and skimmed milk. The incidence of post-operative VTE decreased markedly during the Second World War in Norway followed by a marked increase after the war.(48) Likewise, the autopsy incidence of fatal pulmonary embolus over time in Heidelberg, Germany showed a clear relationship between fatal pulmonary embolism and wartime conditions. The lowest incidence of fatal pulmonary embolus, expressed as a percentage of all hospitalized patients, was registered during the post-Second World War years with a relative and absolute minimum between 1945 and 1949. The 1947 value (0.04%) was an order of magnitude lower than in 1932 (0.45%) or 1955 (0.38%) (Fig. 1).(49) Food rationing in Europe did not end until the early 1950s.
Figure 1. Fatal PE cases from 1915 to 1964 in Heidelberg, Germany.(46) Absolute numbers of patients with autopsy-proven fatal PE in black.(47)
In Vienna in the early 1930s, fatal pulmonary embolus accounted for about 1.6% of deaths whose causes were determined by autopsies. In the late 1940s, incidence of fatal pulmonary embolus at autopsy was <1% while it rose to almost 8% by the early 1970s. (Fig. 2) (44)
Figure 2. Vienna, Austria percentages of autopsies with fatal PE.(46, 48)
There are limits to the conclusions that can be drawn from these historical studies, but they suggest that the high-complex-carbohydrate, low animal product diet associated with wartime food rationing and perhaps increased exercise may have markedly reduced the tendency to form thrombi and/or lessened the consequences of those thrombi that did form. Judging from the autopsy data, the effects of these lifestyle influences on VTE risk had a rapid onset and offset. Wartime conditions afforded substantial protection against VTE, especially fatal pulmonary embolus.
Medical literature studies regarding diet and VTE
Paul Agutter, MD, Colm Malone, MD, John Pezzullo, PhD and I reviewed the medical literature looking for scientific evidence that diet in humans makes a difference in the risk of VTE occurrence.(49) We found that, although therapeutic diets are widely suggested for prophylaxis and treatment of arterial cardiovascular disease, healthy nutrition as an approach to prophylaxis and treatment of VTE has never been officially recommended. Acting U.S. Surgeon General Dr. Steven Gaston noted in his 2007 call to action to prevent VTE that the “Longitudinal Investigation of Thromboembolism Etiology” study(50) found a diet with more fruits, vegetables, and fish, and less red and processed meat to be associated with a lower VTE incidence. He suggested further studies on the impact of diet and other lifestyle changes regarding VTE.(51)
After systematically analyzing the clinical and laboratory data, we concluded that the American Heart Association (AHA) step 1 and step 2 low fat diets (fruits, vegetables, lean meat, low fat dairy, eggs, etc.(52)) would not be good candidates for a low VTE risk diet. However, we found that the Mediterranean diet (lots of fruits, vegetables, nuts, fish, and olive oil), vegetarian diets (no beef, pork, fowl, or fish), and vegan diets (no animal products) would be good candidates for a low VTE risk diet. These diets are far from wartime rations, but all have less animal products, particularly red meat.
One of these diets might be considered in Ms. Clinton’s case. These findings during wartime in European cities suggest that diets low in animal products would probably lower incidences of cardiovascular diseases generally and of several kinds of cancers.(44, 45, and 46)
Ms. Clinton is at great risk of major bleeding by taking warfarin. This should be reconsidered in the light of the above discussion.
For the vast majority of otherwise healthy CVT and VTE patients, these diseases run their courses by themselves without anticoagulants and leave the patients as well as they were before. The preliminary evidence on Mediterranean, vegetarian, and vegan diets reducing the risk of VTE together with the evidence of reduced fatal pulmonary embolus in Europe during wartime food rationing suggest that adopting one of these diets might reduce Ms. Clinton’s VTE and overall cardiovascular disease risks.
I hope Ms. Clinton never has another venous thrombosis episode. If she does have another one and she remains otherwise healthy, she will be most likely recover without anticoagulant drugs and without permanent sequellae. For her sake and the sake of other CVT and VTE patients as well as the integrity of our processes and policies of adhering to medical science, we need the leaders of the public and private institutions responsible for the CVT and VTE clinical practice guidelines to address the challenges to the clinical practice guidelines calling for anticoagulants for VTE.
Retracting guidelines for anticoagulant treatment of CVT and VTE could save Ms. Clinton’s life and that of many others.
Acknowledgement: My thanks to John Pezzullo, PhD (biostatistician) for his help with the calculations of risk.
- Bardack L Healthcare Statement regarding Hillary Rodham Clinton. July 28, 2015http://online.wsj.com/public/resources/documents/clintonhealth2015.pdf
- Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, et al. (2012) Antithrombotic Therapy for VTE Disease. Chest 141: e419S-e494S. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/
- Saposnik G, Barinagarrementeria F, Brown RD, Bushnell CD, Cucchiara B,Cushman M, et al. (2011) Diagnosis and Management of Cerebral Venous Thrombosis: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 42: 1158-1192. http://stroke.ahajournals.org/content/42/4/1158.full.pdf
- Cundiff DK (2014) Anticoagulants for Cerebral Venous Thrombosis: Harmful to Patients? Stroke 45: 298-304 https://stroke.ahajournals.org/content/45/1/298.extract
- Cundiff DK (2004) Anticoagulation Therapy for Venous Thromboembolism. MedGenMed 6. http://www.medscape.com/viewarticle/487577
- Cundiff DK, Manyemba J, Pezzullo JC (2006) Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism. The Cochrane Database of Systematic Reviews. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003746.pub2/abstract
- Coutinho J, de Bruijn S, deVeber G, Stam J (2011) Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database of Systematic Reviews: Art. No.: CD002005. http://www.update-software.com/bcp/wileypdf/en/cd002005.pdf
- Barritt DW, Jordan SC (1960) Anticoagulant drugs in the treatment of pulmonary embolism — A controlled trial. Lancet 1: 1309-1312. http://whistleblowerdoctor.org/wp-content/uploads/2015/04/Barritt-and-Jordan1960Lancet.pdf
- Ferro JM, Canhao P, Bousser M-G, Stam J, Barinagarrementeria F, et al. (2005) Cerebral Vein and Dural Sinus Thrombosis in Elderly Patients. Stroke 36: 1927-1932. http://stroke.ahajournals.org/content/36/9/1927.full
- Selim M (2014) Cerebral Venous Thrombosis: Another Heparin Controversy. Stroke 45: 8-9. http://stroke.ahajournals.org/content/45/1/8.full
- Misra UK KJ, Bhoi SK (2014) Letter by Misra et al Regarding Article, “Anticoagulants for cerebral venous thrombosis: harmful to patients?”. Stroke 45: STROKEAHA.114.005410 published online before print April 005417 002014. http://stroke.ahajournals.org/content/early/2014/04/17/STROKEAHA.114.005410
- Stam J (2014) Letter by Stam Regarding Article, “Anticoagulants for Cerebral Venous Thrombosis: Harmful to Patients?”. Stroke. http://stroke.ahajournals.org/content/early/2014/03/06/STROKEAHA.114.004669.short
- Coutinho J, Bousser MG, Stam J (2013) Response to Evidence-Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Stroke 44: e68. http://stroke.ahajournals.org/content/44/6/e68.extract
- Ferro JM, Canhão P (2013) Evidence Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Letter to Editor. Stroke 44: e150 http://stroke.ahajournals.org/content/44/11/e150.long
- Cundiff DK (2014) Response to Letter Regarding Article, “Anticoagulants for Cerebral Venous Thrombosis: Harmful to Patients?”. Stroke 45: e64. http://stroke.ahajournals.org/content/early/2014/03/06/STROKEAHA.114.005007.short
- Cundiff DK (2014) Letter by Cundiff Regarding Editorial, “Cerebral Venous Thrombosis: Another Heparin Controversy”. Stroke 45: e65. http://stroke.ahajournals.org/content/early/2014/02/11/STROKEAHA.114.004703.short
- Cundiff DK (2013) Evidence Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Reply by David K. Cundiff. Stroke 44: e151. https://stroke.ahajournals.org/content/44/11/e151.extract
- Cundiff DK (2013) Evidence-Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Stroke 44: e67 http://stroke.ahajournals.org/content/44/6/e67.full
- AHA/ASA website re guidelines correspondence. . http://my.americanheart.org/professional/StatementsGuidelines/PoliciesDevelopment/Correspondence/Correspondence_UCM_320919_Article.jsp
- AHA/ASA Support from Pharmaceutical Companies and Device Manufacturers and American Heart Association Total Corporate Support 2013-2014. American Heart Association.
- Talarico L, Temple R (2001) Letter regarding anticoagulants for venous thromboembolism to David K. Cundiff, MD. In: Division of Gastrointestinal and Coagulation Drug Products FaDA, editor. http://whistleblowerdoctor.org/wp-content/uploads/2015/04/Robert-Temple-re-AC-for-VTE.pdf
- (1990) Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 263: 2753-2759. http://jama.jamanetwork.com/article.aspx?articleid=381954
- Kakkar VV, Flanc C, O’Shea M, Flute P, Howe CT, et al. (1968) Treatment of deep-vein thrombosis–a random trial. Br J Surg 55: 858. http://www.ncbi.nlm.nih.gov/pubmed/4879792
- Cundiff DK (2007) Evidence-based Medicine and the Cochrane Collaboration on Trial. MedGenMed 9: 56. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994886/
- Cundiff D (2006) Money Driven Medicine–Tests and Treatments That Don’t Work. http://www.grandbargainsbook.com/money-driven-medicine/
- Tovey D (Cochrane) Editor in Chief’s response to a review by Dr David Cundiff in The Medscape Journal of Medicine. Cochrane Editorial Unit. http://editorial-unit.cochrane.org/sites/editorial-unit.cochrane.org/files/uploads/Editor_in_chief_response_to_David_Cundiff.pdf
- Cundiff DK (2009) A systematic review of Cochrane anticoagulation reviews. Medscape J Med 11. http://www.medscape.com/viewarticle/584084
- About David K. Cundiff. WhistleblowerDoctor.org. http://whistleblowerdoctor.org/about-david-cundiff/
- Nielsen HK, Husted SE, Krusell LR, Fasting H, Charles P, et al. (1994) Anticoagulant therapy in deep venous thrombosis. A randomized controlled study. Thrombosis Research 73: 215-226. http://www.ncbi.nlm.nih.gov/pubmed/8191414
- Ott P, Eldrup E, Oxholm P (1988) The value of anticoagulant therapy in deep venous thrombosis in the lower limbs in elderly, mobilized patients. A double-blind, placebo-controlled investigation with open therapeutic guidance. Ugeskr Laeger 150: 218-221. http://www.ncbi.nlm.nih.gov/pubmed/?term=3287734
- Cundiff DK (2008) Clinical evidence for rebound hypercoagulability after discontinuing oral anticoagulants for venous thromboembolism. Medscape J Med 10: 258. http://www.medscape.com/viewarticle/582408
- Cundiff DK, Agutter P, Malone P, Pezzullo J (2010) Diet as prophylaxis and treatment for venous thromboembolism? Theoretical Biology and Medical Modelling. http://www.tbiomed.com/content/7/1/31/comments
- Deep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) — Blood Clot Forming in a Vein: Data & Statistics. In: Center for Disease Control, editor.
- Deitelzweig SB, Johnson BH, Lin J, Schulman KL. (2011) Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 86: 217–220. http://www.ncbi.nlm.nih.gov/pubmed/21264912
- Spyropoulos AC, Lin J (2007) Direct Medical Costs of Venous Thromboembolism and Subsequent Hospital Readmission Rates: An Administrative Claims Analysis From 30 Managed Care Organizations J Manag Care Pharm 13: 475-486. http://www.amcp.org/data/jmcp/pages%20475-86.pdf
- Mahan CE, Borrego ME, Woersching AL, Federici R, Downey R, Tiongson J, et al. (2012) Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates. Thromb Haemost 108: 291-302. http://www.ncbi.nlm.nih.gov/pubmed/22739656
- Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, et al. (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158: 585-593. http://archinte.jamanetwork.com/article.aspx?articleid=191629
- Spencer FA, Emery C, Joffe SW, Pacifico L, Lessard D, et al. (2009) Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE Study. Journal of thrombosis and thrombolysis 28: 401-409. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248815/
- White R, Zhou H, Romano P (1998) Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 128: 737 – 740. http://www.ncbi.nlm.nih.gov/pubmed/9588434
- Coutinho JM, Zuurbier SM, Aramideh M, Stam J (2012) The Incidence of Cerebral Venous Thrombosis: A Cross-Sectional Study. Stroke 43: 3375-3377. http://stroke.ahajournals.org/content/43/12/3375.abstract
- Beckman MG, Hooper WC, Critchley SE, Ortel TL (2010) Venous Thromboembolism. American Journal of Preventive Medicine 38: S495-S501. http://www.ajpmonline.org/article/S0749-3797(09)00946-5/pdf
- Carrier M, Le Gal G, Wells PS, Rodger MA (2010) Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 152: 578. http://annals.org/article.aspx?articleid=745761
- Linkins L , O’Donnell M , Julian JA , Kearon C (2010) Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. J Thromb Haemost 8: 2201 – 2207. http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2010.04016.x/pdf
- Malmros H (1950) Acta Med Scand 246: 137. http://www.ncbi.nlm.nih.gov/pubmed/14789502
- Strom A (1948) Examination into the diet of Norwegian families during the war-years 1942– 45. Acta Med Scand Suppl 214: 1– 47.
- Sigg K (1976) Varicen, Ulcus cruris und Thrombosen. Berlin, Heidelberg, and New York: Springer-Verlag.
- Linder F, Schmitz W, Encke A, Trede M, Storch H (1967) A study of 605 fatal pulmonary embolisms and two successful embolectomies. Surg Gynecol Obstet 125: 82-86. http://www.ncbi.nlm.nih.gov/pubmed/6026688
- Nielsen H, Bechgaard P, Nielsen P, Husted S, Geday E (1981) 178 fatal cases of pulmonary embolism in a medical department. Acta Med Scand 209: 351-355. http://www.ncbi.nlm.nih.gov/pubmed/7246271
- Cundiff D, Agutter P, Malone P, Pezzullo J (2010) Diet as prophylaxis and treatment for venous thromboembolism? Theoretical Biology and Medical Modelling 7. http://www.tbiomed.com/content/7/1/31
- Steffen L, Folsom A, Cushman M, Jacobs D, Rosamond W (2007) Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology. Circulation 115: 188-195. http://circ.ahajournals.org/cgi/reprint/115/2/188
- Gaston S (2008) The Surgeon General’s call to action to prevent deep vein thrombosis and pulmonary embolism. U.S. Department of Health and Human Services.
- Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, et al. (2000) AHA Dietary Guidelines: Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association. Circulation 102: 2284-2299. http://circ.ahajournals.org/content/102/18/2284.full