A Systematic Review of Cochrane Anticoagulation Reviews

Abstract

Context

I coauthored a published review of anticoagulation for venous thromboembolism in the Cochrane Database of Systematic Reviews and published a review on the same topic in MedGenMed (now the Medscape Journal of Medicine). In contrast to the article in Medscape, the discussion and conclusions in the Cochrane review were altered appreciably during the review process. Consequently, I decided to critique all anticoagulation drug-related reviews and protocols in the Cochrane database with feedback letters concerning any issues of potential controversy.

Evidence Acquisition

Using key words in the search engine of the Cochrane Reviews, I located reviews and protocols involving anticoagulant drugs. I critiqued each anticoagulation review and protocol and sent a total of 57 feedback letters to Cochrane concerning each publication to elicit a response/rebuttal from the authors.

Evidence Synthesis

Cochrane anticoagulation review editors acknowledged receipt of all letters. As of 12 months after receipt of my last letter, the Cochrane authors have replied to 13 of the 57 and agreed with many of my points. Two protocols were withdrawn after my feedback letters were acknowledged. The 58 Cochrane anticoagulation drug reviews, including mine, contained 9 categories of methodological errors (207 total instances) and 4 types of biases (18 total instances). This review of those Cochrane reviews suggests that the effectiveness of anticoagulants for 30 medical indications is questionable.

Conclusions

The efficacy of anticoagulants for treatment and prophylaxis for 30 current medical indications should be reconsidered by the scientific community and medical regulatory agencies. At least 50,000 people per year worldwide have fatal bleeding due to anticoagulant treatment or prophylaxis for these indications.

Introduction

In January 2006, the Cochrane Database of Systematic Reviews included a review that I coauthored: “Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism (VTE).”[1] Our first draft of the Implications for Practice section stated, “Anticoagulants are not evidence-based to be safe and effective in reducing morbidity and mortality in patients with VTE.” For the “Implications for Research” section, we suggested conducting a non-inferiority RCT to compare standard anticoagulants with an NSAID to see whether an NSAID (ie, platelet inhibitor) could be equally effective but safer and less expensive.

However, after editing by the peer reviewers and editor, the “authors conclusions” were, “The limited evidence from RCTs of anticoagulants versus 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 further RCT comparing anticoagulants to placebo could not ethically be carried out.”

My review of anticoagulant treatment for VTE published in MedGenMed (now Medscape Journal of Medicine) in 2004 gave a completely different analysis, questioning the efficacy of anticoagulant treatment for VTE.[2]

That experience suggested that systematically critiquing all the Cochrane reviews and protocols involving anticoagulant drug interventions might be useful to see whether other methodological errors or biases exist.

Methods

Data Sources

I used the Cochrane Database of Systematic Reviews, 2007, Issue 3, to search for protocols and completed reviews about treatment with anticoagulant drugs. In following up with responses to my feedback letters, I searched the Cochrane Database of Systematic Reviews, 2008, Issue 4. Search terms were “anticoagulant,” “heparin,” “vitamin K inhibitor,” “vitamin K antagonist,” and “warfarin.”

Study Selection

All reviews and protocols that studied anticoagulant drugs or included recommendations for or against use of anticoagulant drugs, including my review, were evaluated. No reviews or protocols were excluded.

Data Extraction

I submitted a formal complaint to the Cochrane disputes editor in September 2006 about the editing of the review that I coauthored (Table 1 #1). I critiqued the other 57 reviews and protocols and sent in feedback letters to the authors. This served as an opportunity for Cochrane to respond to the points of contention concerning my review. After finishing all 58 critiques, I derived 9 categories of methodological errors and 4 types of biases in reporting and/or interpreting data that recurred in at least 2 reviews.

Table 1.

Cochrane Anticoagulation Drug Reviews^*

1	Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism[1]
Highlight(s) of feedback letter
See the Introduction See also Results section: Categories of Methodological Errors and Biases #4 – RCTs are too small to evaluate risk for HITT and observational studies not evaluated for HITT. My published commentary, “Evidence-based Medicine and the Cochrane Collaboration on Trial”[68] comprehensively details the points of contention in this review:
2	Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism[69]
Highlight(s) of feedback letter
The objective of the review is, “To evaluate the efficacy and safety of long-term treatment of VTE with low-molecular-weight heparins compared to vitamin K antagonists.” However, neither anticoagulant has been shown to be effective compared with unanticoagulated controls, so this review evaluates the efficacy and safety of neither.
3	Low molecular weight heparin for prevention of venous thromboembolism in patients with lower leg immobilization.[70]
Highlight(s) of feedback letter
The primary efficacy endpoint combines asymptomatic and symptomatic VTE. This means that it relies primarily on the more frequent surrogate endpoint asymptomatic DVT. Only a purely clinical endpoint should be used to measure efficacy. Even symptomatic VTE would be inappropriate as the sole primary outcome measure to determine recommendations, since it does not include adverse events (ie, bleeding). Combining symptomatic and fatal VTE and fatal complications of the LMWH (major bleeding and HITT) would be the most clinically relevant primary endpoint. Because of excluding observational studies from consideration in the safety analysis, the bleeding complications will very likely be understated. Rebound hypercoagulability was not assessed. The review was published 14 months after my critique of the protocol was received and acknowledged. My points were not addressed.
4	Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism[3]
Highlight(s) of feedback letter
See Results section: Categories of Methodological Errors and Biases #1 – In a meta-analysis of non-inferiority trials, the control group is not evidence-based to be safe and effective. Consequently, non-inferiority does not indicate safety or efficacy.
5	Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment.[45]
Highlight(s) of feedback letter
See Results section: Categories of Methodological Errors and Biases #7 – The primary endpoint, which determines the main conclusions of the review, is a surrogate rather than a clinical endpoint.
6	Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery[51]
Highlight(s) of feedback letter
Authors' conclusions: Implications for Practice section, “Patients receiving venous femoropopliteal, infragenicular bypasses seem to benefit more from VKA than from ASA.” Comment: No differences in clinical endpoints were seen in placebo-controlled RCTs while both drugs were associated with unacceptable rates of fatal bleeding (VKAs, 16 [1.2%], aspirin/dipyridamole, 12 [0.9%]). Rebound hypercoagulability was not assessed. See also Results section: Categories of Methodological Errors and Biases #11 – A patented, expensive treatment (not the subject of the review) that is not evidence-based to work is endorsed in the Implications for Practice section.
7	Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism[71]
Highlight(s) of feedback letter
See Results section: Categories of Methodological Errors and Biases #5 – Rebound hypercoagulability was not assessed by collecting study data for at least 2 months after anticoagulant withdrawal in most patients This is a meta-analysis of non-inferiority trials in which neither the control group (shorter-duration VKA treatment) nor the experimental group (longer-duration VKA treatment) is evidence-based to be safe and effective.
8	Once versus twice daily LMWH for the initial treatment of venous thromboembolism.[72]
Highlight(s) of feedback letter/reply/rebuttal
This is a meta-analysis of non-inferiority trials in which neither the control group (once-per-day LMWH) nor the experimental group (twice-per-day LMWH) is evidence-based to be safe and effective.
9	Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures[15]
Highlight(s) of feedback letter/reply/rebuttal
Implications for Practice: “… (We) recommend that injectable anticoagulants should be reserved for patients at higher risk of thrombosis and those with contraindications to physical methods and/or aspirin (Scottish Intercollegiate Guidelines Network 2002)”. My comment: There is no evidence basis for this statement, although it is drawn from another guidelines-producing group (Scottish Intercollegiate Guidelines Network [SIGN]). Authors reply: “….as we state in the review, the source for the recommendation you refer to is the Hip Fracture Guideline Development Group. Prevention and management of hip fracture in older people. A national clinical guideline (No. 56). Edinburgh: Scottish Intercollegiate Guidelines Network (www.sign.ac.uk), 2002.” My response: Cochrane systematic reviews are supposed to base conclusions and recommendations on RCTs and other published literature, not non-evidence-based opinions of other authorities. See also Results section: Categories of Methodological Errors and Biases #9 – Intracranial bleeding was not separately included in the primary or secondary endpoints.
10	Heparin for prevention of venous thromboembolism in general medical patients (excluding stroke and MI) (Protocol)[73]
Highlight(s) of feedback letter
See Results section: Categories of Methodological Errors and Biases #5 – Rebound hypercoagulability was not assessed. Because observational, population-based, and/or case-control studies were excluded from consideration in the safety analysis, the bleeding complications were very likely understated. The primary endpoints (DVTs and PE demonstrated on venograms and noninvasive scans) are surrogates rather than clinical endpoints. Asymptomatic VTE does not correlate with fatal PE.
11	Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair (Protocol)[74]
Highlight(s) of feedback letter/reply/rebuttal
Standard prophylactic anticoagulation (typically 7–10 days: the control group) following total hip or knee replacement or hip fracture repair provides no proven survival benefit. Anticoagulation does cause significant risks for bleeding and rebound hypercoagulation events. Rebound hypercoagulability events were missed in the extended duration of anticoagulant group (about 30 days of low-dose heparins or other drugs) of this review, thus biasing the findings. In a meta-analysis of RCTs involving VTE prophylaxis of total hip replacement patients, the crude risks for clinically important bleeding (usually wound hematoma) were 0% for compression stockings, 0.3% for controls, 0.4% for aspirin, 1.8% for LMWH, and 2.6% for unfractionated heparin.[75] Because of the seriousness of wound hematomas and the frequently associated infections in these patients, SIGN changed the hip fracture and hip and knee replacement surgical VTE prophylaxis guidelines from advising anticoagulants to advising aspirin.[76]
12	Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high risk patients[77]
Highlight(s) of feedback letter
The primary endpoints, DVTs on venograms and noninvasive scans, are surrogate rather than clinical endpoints. Asymptomatic DVTs do not correlate with fatal PE. Rebound hypercoagulability events were not assessed.
13	Low molecular weight heparins or heparinoids versus standard unfractionated heparin for acute ischemic stroke[4]
Highlight(s) of feedback letter/reply/rebuttal
Despite the absence of benefit of LMWH for any of the major clinical endpoints (death, vascular death, disability), the Implications for Practice appear to justify the use of LMWH and heparinoids in some cases of acute ischemic stroke on the basis of the nonstatistically significant superiority of LMWH and heparinoids over UH in DVT and PE. The Implications for Practice section should read, “Do not use any anticoagulants in patients with acute ischemic stroke.” Likewise, the Implications for Research section should say, “It would be unethical to conduct further trials of anticoagulants in patients with acute ischemic stroke.” Authors' reply: “The first version of the review was prepared at a time when there was uncertainty about the overall effects of heparins in acute ischemic stroke. Since then, as the commenter states, evidence has emerged which shows that there is no net benefit from the immediate anticoagulation in this setting. However, as is often the case, this evidence did not alter the beliefs of some clinicians, and hence, heparin is still used in some countries, in certain types of patient with acute ischemic stroke, for specific reasons and especially for prevention of venous thromboembolism. This review is now based on the premise that if a clinician plans to treat a patient for some special reason with some form of heparin then the choice of agent should be evidence based.” My rebuttal: I question that premise as a basis for a Cochrane Review. Heparin is dangerous. If it is not evidence-based to improve clinical outcomes, don't prescribe it.
14	Anticoagulants versus antiplatelet agents for acute ischemic stroke[78]
Highlight(s) of feedback letter
The authors correctly point out that there was no statistically significant increase in major extracranial or intracranial hemorrhage (OR, 1.82 [95% CI, 0.87–3.81] and OR, 1.46 [95% CI, 0.72–2.97], respectively). However, when these 2 categories of major hemorrhage are combined, there is a borderline statistically significant increase in major bleeding (OR, 1.63 [95% CI, 0.98–2.72]; P< .06), which represents 6.2 additional major bleeding episodes per 1000 patients (95% CI, - 0.1 to 16.8) by adding the low-dose heparin. Risk for bleeding in clinical practice is probably greater than in closely monitored RCTs. Since adding low-dose heparin to aspirin does not improve clinical outcomes and does add to the bleeding risk, the Implications for Research section should say that further trials of any anticoagulants in acute ischemic stroke would be unethical and any studies under way should be stopped. Also see Results section: Categories of Methodological Errors and Biases example #9 – Fatal bleeding was not separately included in the primary or secondary endpoints.
15	Anticoagulants for acute ischemic stroke[79]
Highlight(s) of feedback letter
This review of anticoagulant trials, including over 22,000 patients with acute ischemic stroke, found no net benefit with the use of any anticoagulant. The Implications for Practice section should say that anticoagulants should be contraindicated in patients with acute ischemic stroke. The Implications for Research section should say that further trials of anticoagulants in acute ischemic stroke would be unethical.
16	Anticoagulants for preventing recurrence following presumed non-cardioembolic ischemic stroke or transient ischemic attack[80]
Highlight(s) of feedback letter
This Cochrane Review should be updated to indicate that VKA treatment should be contraindicated in patients with acute ischemic stroke. In 2005, the Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) trial was terminated early because of the high incidence of death in the warfarin group (9.7% in the warfarin group vs 4.3% in the aspirin group; hazard ratio for aspirin relative to warfarin, 0.46; 95% CI, 0.23 to 0.90; P=.02).[53] The authors concluded, “Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.” No further anticoagulant drug research is warranted in this patient group.
17	Antiplatelet therapy for acute ischemic stroke[81]
Highlight(s) of feedback letter
The review concluded that aspirin significantly decreases death and dependency in stroke patients. The Implications for Research section states, “… There is also a case for further trials of low dose subcutaneous heparin (or low dose low molecular weight heparin) plus aspirin versus aspirin alone in the prevention of post-stroke deep vein thrombosis and pulmonary embolism, and in reducing neurological disability from the original or recurrent strokes. Such trials would need to include several tens of thousands of patients.” My comment: This review should be updated to reflect that, given the lack of efficacy of anticoagulants in multiple trials and high bleeding risk in stroke patients (see #16 above), further trials with low-dose heparin or low-dose LMWH would be unethical.
18	Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm.[82]
Highlight(s) of feedback letter
Authors' conclusions in the “Implications for Practice” section: “The thromboprophylactic benefits of aspirin in patients with heart failure who are in sinus rhythm are not convincing, but may be detrimental in view of the reduction of ACE Inhibitor benefit and other side effects. It should be emphasized that the evidence for a potential interaction between ACE inhibitors and antiplatelet agents is mainly based on nonrandomized studies, in light of the quality of the studies from which the data are derived and the post hoc nature of the study analyses, the possible interaction should be interpreted with caution.” My comment: The implications for practice are obfuscation – do not prescribe antiplatelet agents! The abstract of the WASH trial (the only trial reviewed in this review) concludes, “The benefits of warfarin for patients with heart failure in sinus rhythm have not been established. Antithrombotic therapy in patients with heart failure is not evidence based but commonly contributes to polypharmacy.” Whereas, VKA therapy for heart failure has been tested and is not evidence-based to work, this review gives the false impression that the jury is out and that such treatment may be reasonable. Adverse events due to rebound hypercoagulability were not monitored.
19	Anticoagulation for heart failure in sinus rhythm.[23]
Highlight(s) of feedback letter
See Results section: Categories of Methodological Errors and Biases example #2 – The control group of the RCT (aspirin for heart failure) is evidence-based to do harm.
20	Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery[83]
Highlight(s) of feedback letter
The Implications for Practice section focuses on beneficial therapies for subgroups of patients: (1) patients with venous graphs and (2) patients with artificial graphs. These subgroups were not defined in the protocol, so post hoc statistical analyses of outcomes of these subgroups should not be emphasized in the Results or Conclusions. In several places, the Cochrane Handbook warns against problems with post hoc analyses – for example, page 63: “Post-hoc questions are more susceptible to bias than those asked a priori, and data-driven questions can generate false conclusions based on spurious results.” Adverse events due to rebound hypercoagulability were not monitored.
21	Anticoagulants (heparin, LMWHs, and oral anticoagulants) for intermittent claudication[84]
Highlight(s) of feedback letter
No benefit was shown in any clinical parameter for claudication patients. The anticoagulants increased bleeding, including at least 1 case of fatal bleeding. Rebound hypercoagulation adverse events were not assessed. Further research of anticoagulants for claudication is inappropriate and unethical.
22	Oral anticoagulation for prolonging survival in patients with cancer[5]
Highlight(s) of feedback letter/reply/rebuttal
A major conclusion of the review: Oral anticoagulation prolongs life in people with extensive small-cell lung cancer. My comment: The survival in small-cell lung cancer was based on a post hoc statistical analysis. Author reply: It was an a priori determined subgroup, because the protocol states, “We will try to explain heterogeneity, if present, by conducting subgroup analyses. Our a priori factors to explain heterogeneity are the characteristics of participants… and we list ‘type/location of cancer’ as a patient characteristic.” My rebuttal: If all cell types of cancer were designated for subgroup analysis by this catch-all statement, then adjusting for multiple comparisons (eg, Bonferroni adjustment) would render the P value for the benefit of extensive small-cell lung cancer with oral anticoagulants insignificant. The authors' reply to my rebuttal is pending.
23	Anticoagulants for preventing stroke in patients with nonrheumatic atrial fibrillation (NRAF) and a history of stroke or transient ischemic attack[85]
Highlight(s) of feedback letter
The authors' concluded, “The evidence suggests that anticoagulants are beneficial, without serious adverse effects, for people with NRAF and recent cerebral ischemia.” Although neither of these small RCTs with careful selection of relatively young patients had intracerebral bleeding (ie, for the 500-plus subject-years of follow-up on anticoagulants), about 12 such bleeding events would be expected in a general practice setting with a similar number of patient-years on anticoagulants.[43] The relatively younger age of patients in these RCTs means that efficacy in preventing vascular events will also be lower than in general practice. Adverse events due to rebound hypercoagulability were not monitored.
24	Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack[39]
Highlight(s) of feedback letter
Authors' conclusion: “The evidence from two trials suggests that anticoagulant therapy is superior to antiplatelet therapy for the prevention of stroke in people with NRAF and recent non-disabling stroke or TIA. The risk of extracranial bleeding was higher with anticoagulant therapy than with antiplatelet therapy.” See Results section: Categories of Methodological Errors and Biases #6 – Because of excluding observational, population-based, and/or case-control studies from consideration in the safety analysis, the bleeding complications were very likely understated. Fatal and intracranial bleeding were not reported Adverse events due to rebound hypercoagulability were not monitored.
25	Home versus in-patient treatment for deep vein thrombosis[86]
Highlight(s) of feedback letter
Authors' plain language summary: “Home treatment of deep vein thrombosis (DVT) is cost effective and preferred by people with DVT.” Hospital treatment of DVT with anticoagulants (the control group) is not evidence-based to be safe or effective.[1,68,87–89] Therefore, home anticoagulation treatment for DVT (the experimental group) is not proven to be safe and effective.
26	Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period[90]
Highlight(s) of feedback letter
The relevant issue: As it stands, the guidelines for anticoagulation during pregnancy and the postpartum period by the American College of Chest Physicians[91] and the Royal College of Obstetricians and Gynaecologists[92] are arguably the standard of care in the United States and United Kingdom, respectively. Despite the lack of RCT evidence, these opinion-based guidelines recommend anticoagulants in many instances, and they can be referenced in medicolegal cases. This review appropriately concludes that anticoagulant thromboprophylaxis during pregnancy is not evidence-based to be safe and effective. However, the implications for practice and research do not go far enough. Since anticoagulation carries risks for bleeding, osteoporosis, and fetal deformity, the appropriate implication for practice would be that thromboprophylaxis with anticoagulants should not be used outside of an RCT. The Implications for Research section should state that any RCTs of anticoagulation in pregnant women should be placebo controlled.
27	Heparin for pregnant women with acquired or inherited thrombophilias.[6]
Highlight(s) of feedback letter/reply/rebuttal
The issue: Despite the lack of RCT evidence, opinion-based treatment guidelines for pregnant women with thrombophilia by the Royal College of Obstetricians and Gynaecologists and the American College of Chest Physicians include thromboprophylaxis.[91,92] My suggestion: “Given the risks of heparin, the implications for practice for the review should say that heparin should not be used for pregnant women with acquired or inherited thrombophilias outside of a placebo or antiplatelet agent controlled RCT.” The lead author agreed to make the change with the next review update.
28	Heparins and mechanical methods for thromboprophylaxis in colorectal surgery[7]
Highlight(s) of feedback letter/reply/rebuttal
Authors' Implications for Practice: “Both unfractionated heparin and low molecular weight heparin can be used as effective prophylaxis against postoperative thromboembolic complications after colorectal surgery.” My comment: These conclusions are based on surrogate endpoints (eg, venograms which mostly show asymptomatic DVTs) rather than clinical endpoints (eg, death, fatal PE, symptomatic VTE). Authors' reply: “We must not forget that the efficacy of heparin prophylaxis against fatal Postoperative PE was established in a methodologically correctly performed trial more than 30 years ago (International Multicentre Trial).[93] Taken these facts in mind I still mean that the use of postoperative prophylaxis is evidence based, and for comparing different methods the use of venography for detecting subclinical DVT as endpoint is scientifically acceptable.” My rebuttal: While methodologically correct for its time, the International Multicentre Trial preceded the era of early mobilization and mechanical VTE prophylaxis. The follow-up period was only until discharge from hospital, so the deaths caused by rebound hypercoagulation after heparin was stopped were missed. Likewise, in this review adverse events due to rebound hypercoagulability were not monitored.
29	Heparin versus placebo for acute coronary syndromes[16]
Highlight(s) of feedback letter/reply/rebuttal
At my suggestion, the authors completed this review 6 years after they published the protocol. The efficacy and safety of LWMH for acute coronary syndromes depends on the evidence basis of heparin vs placebo for acute coronary syndromes. See correspondence for review #30 below See Results section #5 – Rebound hypercoagulability was not assessed by collecting study data for at least 24 hours after heparin withdrawal
30	Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes[8]
Highlight(s) of feedback letter/reply/rebuttal
The appropriateness of this review is predicated on the efficacy of heparins when compared with placebo where all patients are also treated with aspirin. The authors maintain that their recently published Cochrane Review of this topic establishes the benefit of heparin plus aspirin vs aspirin alone. I dispute that contention. (See my feedback letter for #29 above.) If neither LMWH nor UH is evidence-based to be beneficial for people with acute coronary syndromes, comparing them is inappropriate. With additional antiplatelet agents and invasive procedures in recent years, heparins are significantly more hazardous that when the trials in this review were done. Heparins should not be used for acute coronary syndromes outside of placebo-controlled RCTs.
31	Heparin for ST-segment elevation myocardial infarction (Protocol)[94]
Highlight(s) of feedback letter
From the abstract: “The objective of this systematic review is to determine the effectiveness and safety of heparin compared to all other modalities in the treatment of patients with STEMI.” Rebound hypercoagulability-related adverse events should be monitored. Fatal bleeding and/or intracranial bleeding should be separately included in the primary or secondary endpoints.
32	Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks[95]
Highlight(s) of feedback letter
RCTs, like those included in this review, report low bleeding complication rates with VKA treatment (eg, major bleeding/yr = 2.2%; intracranial bleeding/yr =0.5%; fatal bleeding/yr = 0.4% [n = 1939][96]). In contrast, a recent series of consecutive patients started on warfarin for atrial fibrillation reported higher rates of bleeding complications (major bleeding/yr, 7.2%, intracranial bleeding/yr, 2.5%, fatal bleeding/yr, 0.8% [n = 472][43]). Rebound hypercoagulability-related adverse events were not monitored. See also Results section: Categories of Methodological Errors and Biases #10 – Conclusions of review were based on data from RCTs with patients who are not representative of those in general clinical practice.
33	Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischemic attack or minor stroke of presumed arterial origin.[52]
Highlight(s) of feedback letter
See Results section: Categories of Methodological Errors and Biases #12 – This review has not been updated to include the Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) trial.[53] It was terminated early because of the high incidence of death in the warfarin group (4.3% in the aspirin group vs 9.7% in the warfarin group).
34	Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome[97]
Highlight(s) of feedback letter
Plain-language summary: “Insufficient evidence to say if anticoagulants help women with recurrent pregnancy loss without antiphospholipid syndrome” Authors' recommendation: Large, randomized, placebo-controlled trials Given the risks of heparin and the potential for harm, if tens of thousands of women have heparin treatment during pregnancy, the main endpoint in the recommended RCT (anticoagulant vs placebo) should be a live, healthy baby in 2 or 3 pregnancies rather than in a single pregnancy.
35	Oral anticoagulants for the secondary prevention of coronary heart disease (Protocol)[9]
Highlight(s) of feedback letter/reply/rebuttal
My comments on the methods of this protocol were well received. The authors agree to: Add a subgroup in the analysis of patients not in heart failure Highlight the limitations with external validity in the review Evaluate rebound hypercoagulability by extracting data on time since anticoagulant withdrawal Add fatal and intracranial bleeding as secondary endpoints.
36	Self management for oral anticoagulation (Protocol)[98]
Highlight(s) of feedback letter
Rebound hypercoagulability-related adverse events should be monitored. The bleeding complications will very likely be understated unless observational and/or population-based studies are included in the safety analysis. Fatal bleeding and intracranial bleeding should be separately reported and added to the primary or secondary endpoints. Patients and physicians would be particularly interested in these safety measures. This protocol assumes that those oral anticoagulants are evidence-based to benefit patients. However, the critiques of multiple Cochrane reviews in this paper question this assumption.
37	Anticoagulation for cerebral sinus thrombosis[99]
Highlight(s) of feedback letter
The authors implied that heparin is effective for CSVT, although the 2 small trials showed no statistically significant reduction in mortality. The nonsignificant trend depends on a single small trial that was subject to early termination bias. The authors of this CSVT review called heparin safe on the basis of only 40 cases (about 800 days of heparinization). CNS bleeding is a common cause of morbidity and mortality in CSVT, so heparin is not safe. Further placebo-controlled RCTs were inappropriately discouraged (“….patients and doctors may be reluctant to embark upon a new trial that includes a placebo group.”).
38	Interventions for preventing venous thromboembolism in adults undergoing knee arthroscopy[100]
Highlight(s) of feedback letter
Authors' conclusions: “No strong evidence was found to conclude thromboprophylaxis is effective to prevent thromboembolic events and safe, in people with unknown risk factors for thrombosis, undergoing knee arthroscopy.” From plain-language summary: “Adverse events were most common in the intervention group (i.e., anticoagulant prophylaxis). The most common complication was minor bleeding with a RR of 2.23 (range 0.99 to 4.99). The number needed to harm was 20.” From Implications for Research section: “Surveillance studies will be important to assess the detection of both adverse events and thrombotic events, with and without the use of LMWH.” Rebound hypercoagulability-related adverse events were not monitored. The implication for practice should be that anticoagulant prophylaxis should not be used. The implication for research should be that further RCTs with knee arthroscopy patients exposed to anticoagulants would be unethical.
39	Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparin for prevention of venous thromboembolism following total hip or knee replacement or hip repair (Protocol)[101]
Highlight(s) of feedback letter
Anticoagulant prophylaxis statistically significantly benefits surrogate endpoints of DVTs as shown by venograms and other tests, but it has not been shown to improve clinical endpoints (eg, fatal pulmonary emboli, mortality, symptomatic VTE). The control group for this review (VKAs and LMWHs) is not evidence-based to be effective. This proposed meta-analysis of non-inferiority trials comparing VKAs and LMWHs with direct thrombin inhibitors is not appropriate to prove efficacy or safety of direct thrombin inhibitors. The protocol does not call for monitoring for rebound hypercoagulability-related adverse events.
40	Heparin-bonded catheters for prolonging the patency of central venous catheters in children[102]
Highlight(s) of feedback letter
Authors' conclusions: “The use of heparin-bonded catheters is a promising therapy but warrants further studies.” See Results section: Categories of Methodological Errors and Biases #3 – Placebo or no treatment control was used when saline flushes are widely used and are safe and considered effective. The primary endpoint is “Days of catheter patency (duration of patency of first catheter, in days).” The most appropriate clinical endpoint would seem to be occlusion of CVCs. Given the risk for bleeding and HITT, a safety measurement should also be included in a composite primary endpoint. Fatal bleeding and intracranial bleeding should have been designated separately as primary or secondary endpoints because of the magnitude of these events. Rebound hypercoagulability-related adverse events should have been monitored.
41	Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children (Protocol)[103]
Highlight(s) of feedback letter
See Results section of this review: Categories of Methodological Errors and Biases #3 – Placebo or no treatment control was used when saline flushes are commonly employed as an anticlotting measure clinically; saline flushes are safe and considered effective in preventing CVC-related thrombosis in children. The primary outcome measure, “CVC-related thrombosis (along the length of, or at the tip of, the catheter) as determined by either color-coded Doppler ultrasonography or contrast venography,” is a surrogate endpoint rather than a clinically relevant efficacy measurement. Instead, the secondary endpoint, “occlusion of CVC (defined as inability to infuse fluids through the catheter due to blockage),” should be made the primary endpoint. Because RCTs for this indication will probably be too small to evaluate risk for HITT and hemorrhage, observational studies should also be included in the safety analysis. Fatal bleeding and intracranial bleeding should be designated separately in the primary or secondary endpoints because of the particular importance of these events. Rebound hypercoagulability-related adverse events should be monitored.
42	Interventions for preventing venous thromboembolism following abdominal aortic surgery (Protocol)[47]
Highlight(s) of feedback letter
The primary endpoint (symptomatic plus asymptomatic DVT or symptomatic PE) is inappropriate, because asymptomatic DVT (a surrogate endpoint) will dominate. There is no evidence that asymptomatic DVT correlates with clinically important outcomes. See Results section: Categories of Methodological Errors and Biases #8 – The primary endpoint should include major bleeding rather than just VTE. Fatal and intracranial bleeding should be separately designated as primary or secondary endpoints because of the importance of these events. To properly assess adverse events, including major bleeding and HITT, RCTs should be supplemented with large prospective or retrospective observational studies. Rebound hypercoagulability-related adverse events should be monitored.
43	Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks[48]
Highlight(s) of feedback letter
Authors' conclusions: Adjusted-dose warfarin and related oral anticoagulants reduce stroke, disabling stroke, and other major vascular events for those with nonvalvular atrial fibrillation by about one third when compared with antiplatelet therapy. Given the risk for adverse effects with VKAs, major bleeding should be included in a composite primary outcome measure. See Results section: Categories of Methodological Errors and Biases #10 – Conclusions of the review were based on data from RCTs with younger, healthier, and more compliant patients than are typically seen in general clinical practice. Representative safety data will not come from RCTs with anticoagulation researchers carefully monitoring the international normalized ratios of highly selected patients. Large observational studies need to be 1 way to assess the rates of major and fatal bleeding. For example, in this review VKA-related major bleeding (1.6%/yr) and intracranial bleeding (0.45%/yr) were considerably less frequent than in a recent observational study (7.2%/yr. and 2.5%/yr, respectively).[43] Rebound hypercoagulability-related adverse events were not monitored.
44	Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.[10]
Highlight(s) of feedback letter/reply/rebuttal
Authors' conclusion: “This review suggests a survival benefit of heparin in cancer patients in general, and in patients with small cell lung cancer in particular.” My comment: (See Results section: Categories of Methodological Errors and Biases #13) – Biases exist in the selection of trials for inclusion in the review: 12 RCTs were eligible but only 5 were included, so the potentially biased selection of trials makes interpretation of the data “favorable to heparin” highly suspect. Authors' reply: “We agree that it would have been ideal to include data from the trials published as abstracts… Interpretation of the findings of this review is limited by the moderate heterogeneity… The interpretation of findings is also limited by not including data from the 7 trials published as abstracts only.” These qualifications were not added to the abstract or plain-language summary where people without a subscription to the Cochrane Library could read it.
45	Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant[104]
Highlight(s) of feedback letter
Authors' conclusion: “Combined unfractionated heparin and aspirin may reduce pregnancy loss by 54%.” Since all 3 RCTs of aspirin vs placebo showed no benefit, aspirin should be avoided and excluded from future RCTs. Even if adding heparin to aspirin does increase the chances of live birth in a single pregnancy in this situation from 30/70 (43%) to 52/70 (74%), it is not significantly better that the chance of a live birth in 2 pregnancies with aspirin (or placebo) alone (ie, 1 - [0.57 × 0.57] = 68%). Given the risks of anticoagulants, the endpoint of any future RCT should be a healthy baby in 2 or 3 pregnancies rather than 1 pregnancy. Safety (eg, osteopenia, bleeding, HITT, fetal abnormalities) cannot be determined with these small trials (n = 140). The conclusion that heparin added to aspirin increases live births and should become the standard of care in women with recurrent miscarriages associated with antiphospholipid antibodies is premature. In women with recurrent miscarriages, anticoagulants should not be given outside of RCTs.
46	Antiplatelet and anticoagulation for patients with prosthetic heart valves[105]
Highlight(s) of feedback letter
Authors' conclusion: “Adding antiplatelet therapy, either dipyridamole or low-dose aspirin, to oral anticoagulation decreases the risk of systemic embolism or death among patients with prosthetic heart valves. The risk of major bleeding is increased with antiplatelet therapy.” The use of oral anticoagulation itself is not evidence-based to reduce morbidity and/or mortality in patients with prosthetic valves. It is based on anecdotal reports and historical precedent, not RCTs. Even without the addition of aspirin, at least 1% per year of patients taking oral anticoagulants experience fatal bleeding each year. Because adding antiplatelet drugs to oral anticoagulants substantially reduced the risk for thromboembolic events and mortality (61% and 45% respectively), we should have a non-inferiority RCT comparing aspirin alone with aspirin plus a VKA. As a prelude to such a definitive RCT, I am coauthoring a Cochrane protocol titled, “Anticoagulation for prevention of cardiovascular disease in people with prosthetic heart valves.”
47	Antithrombotic drugs for carotid artery dissection[106]
Highlight(s) of feedback letter
Authors' conclusion: “There were no randomized trials comparing either anticoagulants or antiplatelet drugs with control. There is, therefore, no evidence to support their routine use for the treatment of extracranial internal carotid artery dissection…. We suggest that a randomized trial including at least 1400 patients in each treatment group (oral anticoagulants and antiplatelet drugs) with this condition is clearly needed.” Antiplatelet agents – the control group for the primary endpoint comparison in this review (antiplatelet agents vs anticoagulants) – are not evidence-based to reduce death or dependence in people with stroke from carotid artery dissection. However, aspirin and other antiplatelet agents are a potential cause of serious bleeding. Consequently, the Implications for Research section should state that a large RCT of aspirin vs placebo is indicated. Oral anticoagulants should be avoided in carotid artery dissection on the basis of the poor outcome in patient with acute ischemic stroke (Review #16 above).
48	Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters.[107]
Highlight(s) of feedback letter
Primary objective: To assess the effectiveness of heparin for prevention of catheter related thrombosis. Main results: …. “There was no statistically significant difference in the risk of thrombosis (RR 0.93, 95% CI 0.58, 1.51)” … One of 4 secondary endpoints (catheter occlusion) statistically significantly favored heparin. Authors' conclusion: “Evidence from this systematic review support the prophylactic use of heparin for PCVC in neonates at a dose of 0.5 IU/kg/hr.” For this review, the control was placebo or no treatment. A considerable amount of literature attests to the safety and efficacy of saline flushes.[27,28,108] Consequently, saline flushes should have been the control. Safety data from larger observational and case-control studies should have been included to evaluate these potential complications. For example, a case-control study involving 66 neonates with intraventricular bleeding found an increased risk for this devastating complication with heparin use (OR, 3.9 [95% CI, 1.4–11]), after adjusting for other risk factors.[109] Because there was no benefit with heparin for the primary endpoint and considerable risk for devastating intracranial or other bleeding, heparin should not be used.
49	Heparin for prolonging peripheral intravenous catheter use in neonates.[110]
Highlight(s) of feedback letter
Main results: “……Five studies reported data on the duration of use of the first catheter. Two of these studies found no statistically significant effect of heparin; two studies showed a statistically significant increase and one study showed a statistically significant decrease in the duration of PIV catheter use in the heparin group.” Authors' conclusion, Implications for Practice section: “…..Because of clinical heterogeneity and heterogeneity in treatment effect, recommendations for heparin use in neonates with PIV catheters cannot be made.” Authors' conclusions, Implications for Research section: “Further research on the effectiveness, the optimal dose, and the safety of heparin is required.” Premature infants are particularly prone to intracranial hemorrhage. The small number of patients in the 2 RCTs reporting the incidence of intracranial hemorrhage (n = 322) gives no assurance that adding heparin to catheter infusions will not precipitate this dreaded complication. Given that this meta-analysis found no benefit of heparin on first catheter occlusion (n = 485; OR, 1.00 [95% CI, 0.85–1.16]) or any clinical endpoint, further RCTs of heparin in neonates for this indication are not warranted. Heparin should be avoided in premature infants.
50	Ticlopidine versus oral anticoagulation for coronary stenting[11]
Highlight(s) of feedback letter/reply/rebuttal
Authors' conclusions. “Ticlopidine plus aspirin after coronary stenting is effective in reducing the risk of the revascularization, non fatal myocardial infarction and bleeding complications when compared with oral anticoagulants….” My comment: In this meta-analysis of non-inferiority RCTs, the control group, aspirin plus a VKA, has never been shown to improve clinical outcomes for people with coronary stenting. Therefore, it cannot determine the effectiveness and safety of the use of ticlopidine plus aspirin after coronary stenting. The lead author's reply: “The aim of the review was to compare ASA plus ticlopidine versus ASA plus vitamin K antagonists after coronary stenting and not the efficacy and safety of ASA plus ticlopidine per se.”
51	Anticoagulation therapy for pulmonary hypertension (Protocol)[17]
Highlight(s) of feedback letter/reply/rebuttal
The authors withdrew the protocol.
52	Antithrombotic treatment for preventing recurrent stroke due to paradoxical embolism (Protocol)[18]
Highlight(s) of feedback letter/reply/rebuttal
The authors withdrew the protocol.
53	Antiplatelet agents and anticoagulants for hypertension.[12]
Highlight(s) of feedback letter/reply/rebuttal
Safety data concerning VKAs from previous RCTs, observational studies, and population-based studies should supplement the data from the 2 small RCTs in this review. Given the lack of efficacy of warfarin in the RCTs of the review and the likely underestimate of the bleeding risk and unknown risk for rebound hypercoagulation, further RCTs of VKA treatment to reduce vascular events in people with hypertension would be unethical. The authors rebutted my comments challenging the efficacy of platelet inhibitors in secondary prevention of patients with hypertension. Regarding my point that further RCTs of VKA prophylaxis in hypertension, the authors said, “There is inadequate data on warfarin in hypertension per se.”
54	Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer[13]
Highlight(s) of feedback letter/reply/rebuttal
Authors' general observation: “We are not sure what the author [me] refers to being ‘evidence-based,’ but from his comment we believe that s/he has a different understanding of evidence-based. Being ‘evidence-based’ means following the ‘best evidence’ whatever that may be. Evidence can be high quality or lower quality, it can be direct or indirect.” I disagree. By that definition, every test or treatment in medicine is evidence-based. My comment: In this proposed meta-analysis (published as a review after my feedback letter) of RCTs comparing LMWHs with oral anticoagulants, the control group, VKAs, is not evidence-based to be safe and effective. Authors' reply: None My comment: Observational studies were not included in the review to evaluate for HITT and other safety endpoints. Authors' reply: “We will add both HIT and HITT to the list of outcomes to assess.” …..“We have designed the systematic review to include data from RCTs only. We will discuss in the final review the limitation of not including harm data from observational study.” My response: These endpoints were not systematically evaluated in the primary RCTs. My comment: Rebound hypercoagulability-related adverse events were not monitored. Authors' reply: “Dr. Cundiff raises the question, whether the incidence of thrombotic events increases within two months of discontinuing heparin therapy. We will investigate this hypothesis if the studies we include in our review report the relevant data.” My response: No RCTs included these data. My comment: RCTs included in this meta-analysis were subject to selection bias because trials published only as abstracts were not included. Authors' reply: “Dr. Cundiff describes publication bias, which we will investigate as recommended by the Cochrane Collaboration.” My comment: Besides major bleeding, the primary or secondary endpoints should include fatal bleeding and intracranial bleeding because of the particular importance to patients and clinicians of these events. Authors' reply: The 2 proposed outcomes are accounted for by the outcomes listed in our protocol. Fatal bleeding events would be counted as deaths. Intracranial bleeding events would be counted as major bleeding events. My response: Iatrogenic deaths should be counted separately from cancer deaths, and intracranial bleeding rates (fatal and nonfatal) are of special interest to patients and doctors.
55	Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer[111]
Highlight(s) of feedback letter
Comments were very similar to those for review #54. No reply by the authors.
56	Interventions for preventing thrombosis in adults and children with nephrotic syndrome (Protocol)[112]
Highlight(s) of feedback letter
None of the proposed primary outcome measures relate to safety concerns with anticoagulant drugs. The primary endpoint, which determines the main conclusions of the review, should include efficacy and safety measures. Concerning anticoagulants, given the relatively long natural history of the nephrotic syndrome, the slowed metabolism of anticoagulants with renal impairment, the significant bleeding risk, and the paucity of anecdotal evidence of efficacy, the ethics of conducting RCTs with heparins or VKAs should be questioned.
57	Low molecular weight heparin for diabetic kidney disease (Protocol)[14]
Highlight(s) of feedback letter/reply/rebuttal
My comments about adding safety outcomes to this protocol were well received: “The authors agree with your suggestions and have added separate outcomes for: Bleeding (major or fatal bleeding) Anticoagulant-associated intracranial hemorrhage Heparin-induced thrombocytopenia with thrombosis They shall also include all adverse events on one forest plot, but they will be subgrouped and analyzed separately.”
58	Non-immunosuppressive treatment for IgA nephropathy[113]
Highlight(s) of feedback letter
None of the proposed primary outcome measures relate to safety concerns with anticoagulant drugs. The primary endpoint, which determines the main conclusions of the review, should include efficacy and safety measures. Given the relatively long natural history of IgA nephropathy, the slowed metabolism of anticoagulants with renal impairment, the significant bleeding risk, and the paucity of anecdotal evidence of efficacy, the ethics of conducting RCTs with any anticoagulant for any clinical endpoint should be questioned.

ACE = angiotensin-converting enzyme; ASA = acetylsalicylic acid; CI = confidence interval; CNS = central nervous system; CSVT = cerebral sinus venous thrombosis; CVC = central venous catheter; DVT = deep venous thrombosis; HITT = heparin-induced thrombocytopenia with thrombosis; LMWH = low-molecular-weight heparin; MI = myocardial infarction; OR = odds ratio; PCVC = percutaneous central venous catheters; PE = pulmonary embolism; PIV = peripheral intravenous; RCT = randomized, controlled trial; UH = unfractionated heparin; VKA = vitamin K antagonist; VTE = venous thromboembolism. *References to the reviews include links to the abstracts and to my feedback letters.

Validity Assessment

My feedback letters allowed the Cochrane authors of the reviews that I critiqued to rebut or concede the validity of my points. The Cochrane disputes editor was responsible for evaluating my formal complaint about peer-reviewer and editor biases in my review. The Cochrane editors acknowledged all letters and the complaint.

Results

Table 1 lists the titles for each of the Cochrane reviews and the highlight(s) of the feedback letter and authors' reply, if any. Table 2 shows the presence or absence of 13 types of problems corresponding to each review.

Table 2.

Classification of Methodological Errors and Biases

#	Methodological errors in the trials reviewed	#s of reviews/protocols (from Table 1)
1	In a meta-analysis of non-inferiority trials, the control group is not evidence-based to be safe and effective. Consequently, non-inferiority does not indicate safety or efficacy.	1, 2, 4, 5, 6, 7, 8, 11, 12, 13, 18, 19, 20, 25, 30, 31, 34, 39, 45, 46, 47, 50, 54, 55
2	The control group of the RCT is evidence-based to do harm.	19, 35, 50
3	Placebo or no treatment control is used (proposed for protocols) when clearly effective or probably effective nonanticoagulation treatment is either standard therapy or used widely.	37, 40, 41, 48
4	RCTs are (for protocols will be) too small to evaluate risk for HITT and observational studies not (for protocols will not be) evaluated for HITT.	1, 3, 11, 12, 13, 25, 29, 34, 37, 38, 39, 40, 41, 42, 44, 45, 47, 48, 49, 51, 54, 55, 56, 57, 58
5	Rebound hypercoagulability was not (for protocols will not be) assessed by collecting study data for an appropriate length of time after anticoagulant withdrawal in most patients (VTE treatment and prophylaxis, 2 months; heparins for acute coronary syndromes, 24 hours; clopidogrel for acute coronary syndromes or postpercutaneous coronary intervention, 90 days).	1, 3, 5, 6, 10, 11, 12, 24, 25, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 58
6	Because of excluding observational, population-based, and/or case-control studies from consideration in the safety analysis, bleeding complications were (for protocols will be) very likely understated.	1, 3, 9, 10, 11, 13, 24, 25, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58
7	The primary endpoint, which determines the main conclusions of the review, is a surrogate rather than a clinical endpoint.	3, 5, 6, 10, 12, 37, 38, 41, 42, 48, 49
8	The primary endpoint, which determines the main conclusions of the review, should include safety endpoints rather than just efficacy endpoints.	1, 3, 7, 11, 25, 37, 40, 41, 42, 43, 52, 53, 54, 55, 56, 57, 58
9	Fatal bleeding and/or intracranial bleeding were not (for protocols will not be) separately included in the primary or secondary endpoints.	1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58
	Biases in data collection or interpretation by Cochrane reviewers
10	Conclusions of review were based on data from RCTs with patients who are not representative of patients in general clinical practice.	3, 24, 25, 32, 33, 43
11	A patented, expensive treatment (not the subject of the review) that is not evidence-based to work is endorsed in the Implications for Practice section.	5, 6, 46
12	The review has not been updated to include crucial recent RCTs or other data.	14, 33, 47, 48, 49, 50
13	Biases exist in the selection of trials for inclusion in the review.	44, 54, 55

HITT = heparin induced thrombocytopenia with thrombosis; RCT = randomized, controlled trial; VTE = venous thromboembolism

Except for a feedback letter sent June 20, 2001 (Table 1 #4[3]), I sent feedback letters regarding the protocols and reviews from February 2007 through November 2007. As of Issue 4 2008 of the Cochrane Database of Systematic Reviews, Cochrane authors had replied to 13 feedback letters (Table 1 #9, #13, #22, #27, #28, #29, #30, #35, #44, #50, #53, #54, and #57[4–16]). The authors of 1 protocol from 2002 responded to my letter by publishing the review in 2008 (Table 1 #29).[16] Selected highlights of the correspondence on these reviews are included in Table 1. Links to the entire correspondence are included in the references to each review. Two protocols have been withdrawn without any responses to my feedback letters (Table 1 #51 and #52[17,18]).

Cochrane editors from the Heart, Stroke, Pregnancy and Childbirth, and Gynecological Cancer groups indicated that further responses to my feedback letters would be forthcoming.

Categories of Methodological Errors and Biases

Table 1 lists the 58 protocols and reviews involving anticoagulant drugs in the Cochrane Library database as of July 2007. Table 2 shows the categories of methodological errors and biases in articles by review number from Table 1. The following are examples illustrating the 13 categories (references to the reviews include links to the abstracts, to my feedback letters, and to any responses by the authors):

1. In a meta-analysis of non-inferiority trials, the control group is not proven (no evidence base) to be safe and effective. Consequently, non-inferiority does not indicate safety or efficacy.

Efficacy and safety of an experimental drug are established in a non-inferiority trial if the outcomes are not statistically significantly worse than standard treatment. Non-inferiority of an experimental drug compared with an unproven control medication regimen (albeit the standard of care) does not prove that the experimental drug is safe and effective.

For example, in VTE treatment and prevention, heparin and VKAs have been considered the standard of practice since before 1962 when the FDA began requiring rigorous evidence of efficacy before drug approval. Even though the FDA would not approve anticoagulants for VTE if first proposed today, FDA approvals of LMWHs and direct thrombin inhibitors have been based on comparisons with “standard” heparin and warfarin.

However, RCTs comparing heparin and VKAs with no anticoagulation have shown no clinical benefit with anticoagulants. Only 3 small RCTs with properly diagnosed VTE patients have been published, showing a trend toward increased mortality (deaths in VTE patients receiving anticoagulants, 6/66; deaths in VTE patients receiving placebo or NSAIDs, 1/60 [P = .07]).[19–22]

Example #4 (Table 1): Fixed-dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.[3] In this review of RCTs, “standard” heparin is the control therapy for initial VTE treatment. The experimental treatment is any LMWH. Based on the non-inferiority RCTs in the literature, the reviewers concluded that LMWHs are safe and effective as initial treatment for VTE. However, “standard” heparin has never been shown to be effective in reducing morbidity or mortality, so the safety and efficacy of LMWH are unproven.

2. The control group of the RCT is evidence-based to do harm.

In this situation, the experimental group of the trial may show benefit even if the therapy is actually ineffective or harmful.

Example #19 (Table 1): Anticoagulation for heart failure in sinus rhythm.[23] This review of RCTs in heart failure patients compares VKAs with aspirin. Avoiding aspirin is included in the guidelines for treatment of heart failure patients from both the European Society of Cardiology[24] and the American Heart Association/American College of Cardiology.[25] Consequently, using aspirin as the comparator treatment biases the review to favor anticoagulants.

3. Placebo or no-treatment control is used (proposed for protocols) when clearly effective or probably effective nonanticoagulation treatment is either standard therapy or used widely.

In this situation, the experimental drug in the trial may show benefit even if it is has the same or less benefit as a widely used intervention that is safer and/or less expensive.

Example #40 (Table 1): Heparin-bonded catheters for prolonging the patency of central venous catheters in children.[26] In a review of RCTs in heparin bonding in central venous catheters in children to try to keep catheters in place for longer periods, the control group was no treatment. The 2 RCTs included reported no significant difference in duration of catheter patency (primary outcome) or catheter-related thrombosis. The frequency of hemorrhage was not mentioned. The review authors concluded, “Currently available data indicate possible benefits of heparin-bonded catheters; however, further research is needed to establish safety and efficacy.” In other words, there is no evidence for safety or efficacy, yet this review is optimistic about the benefits from heparin-bonded catheters.

However, a commonly used, inexpensive, and probably effective treatment to keep catheters open longer is to periodically flush them with normal saline.[27,28] It is likely that not using saline flushes as the control intervention biased the results of the review in favor of heparin bonding.

4. RCTs are (for protocols will be) too small to evaluate risk of HITT and observational studies were not (for protocols will not be) evaluated for the incidence of HITT.

HITT is uncommon but carries high risks for morbidity and mortality. A true estimate of the risk for HITT requires the monitoring of thousands of patients.

Example #1 (Table 1): Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of VTE.[1] A paragraph suggesting including observational studies to evaluate the risk for HITT in an early draft of my Cochrane VTE protocol was deleted by the peer reviewers and editor. Consequently, we could not attempt to estimate the risk for HITT in heparin use for VTE treatment. Since we found only 126 patients in RCTs of VTE treatment, we could not evaluate the risk for HITT.

5. Rebound hypercoagulability is not considered when determining safety and efficacy.

Several studies describe the resurgence of unstable angina and/or in vitro hypercoagulability on withdrawal from heparins. In vitro evidence of hypercoagulability and a spike in clinical ischemic events in the first 24 hours after discontinuation of heparins has been found.[29–35]

I performed a meta-analysis of 20 RCTs of anticoagulant treatment of VTE in which VTE recurrences were recorded for more than 2 months after discontinuation of the oral anticoagulant. This study showed that the rate of VTE recurrence was much higher in the 2 months following discontinuation of anticoagulants than was subsequently noted (RR, 2.62; 95% CI, 2.19–3.14),[36] suggesting that more than 60% of VTE recurrences in the first 2 months after withdrawal are caused by rebound hypercoagulability. Consequently, the efficacy of anticoagulants in VTE treatment can only be fairly assessed by including event data for at least 2 months after anticoagulant withdrawal in most patients.

Regarding lower doses of anticoagulants as thromboprophylaxis of hospitalized medical and surgical patients, over 100 relatively small RCTs have been published (total number of patients < 5000), all showing no benefit in either PE incidence or survival. Favorable conclusions of these studies toward anticoagulant prophylaxis are based on the use of surrogate endpoints (venograms and noninvasive studies of leg vein clots) that find mostly transient asymptomatic thromboses. Only an RCT published by the Medical Research Council (MRC) in the 1970s showed a statistically significant reduction in fatal PE due to anticoagulant prophylaxis (fatal PE cases out of 4031 patients: thromboprophylaxis = 0, control = 15; P < .05). VTE events after discontinuation of anticoagulation prophylaxis were not reported in the MRC trial or in the others. Additionally, early mobilization, support stockings, and other methods of mechanical prophylaxis have become standard since the 1970s, reducing the incidence of hospital-acquired VTE.

Hoping to determine the efficacy of anticoagulant prophylaxis with a large number of patients in an observational study, Goldhaber and colleagues[37] tracked the incidence of developing DVT or PE after hospitalization in about 80,000 patients admitted over a 2-year period in the Boston's Brigham and Women's Hospital. Out of 13 deaths due to PE that occurred in these patients, 12 had received anticoagulant prophylaxis. Given very conservative assumptions that all fatal PE events occurred in high-risk patients and that half of such patients received anticoagulant prophylaxis, this translates to an estimated increased PE death rate of 12 fold (OR, 12.0; 95% CI, 1.6–92). Only 1 patient without anticoagulant prophylaxis out of 80,000 people hospitalized died of PE, suggesting that the MRC RCT, which was done in the 1970s, is not relevant to current practice.

A similar pattern of rebound adverse vascular events (acute MI and death) has been described in the 90 days after discontinuation of clopidogrel for patients with ACSs or percutaneous coronary interventions.[38]

Unless researchers are aware that rebound hypercoagulability-related events occur with many antithrombotics and record thrombosis recurrences for appropriate times after stopping anticoagulants, RCTs will be biased in favor of antiplatelet agents, oral anticoagulants, heparins, and direct thrombin inhibitors.

Example #29 (Table 1): Heparin versus placebo for acute coronary syndromes.[16] Authors' conclusions: “Compared to placebo, patients treated with heparins had similar risk of mortality, revascularization, recurrent angina, major bleeding and thrombocytopenia. However, those treated with heparins had decreased risk of MI and a higher incidence of minor bleeding.”

However, rebound hypercoagulability negates the benefit of heparin because injectable anticoagulants merely delay a significant portion of heart attacks until after the infusion. The risks for major, permanently disabling, and fatal bleeding with heparin (much greater now than when these studies were done because of greater use of additional antiplatelet drugs and invasive procedures) are not justified by delaying some ischemic events until a day after the infusion is stopped.

6. Because of excluding observational, population-based, and/or case-control studies from consideration in the safety analysis, the bleeding complications were (for protocols will be) very likely understated.

Anticoagulants are among the most risky drugs to use in the medical armamentarium because of the narrow therapeutic window and wide variability in metabolism. Bleeding risk with anticoagulants increases exponentially with age and with several other medical risk factors. Researchers conducting RCTs involving anticoagulants tend to avoid patients at high risk for bleeding. Cochrane meta-analyses of RCTs on anticoagulants frequently have fewer than 1000 persons in each group. With these relatively low numbers, a statistically significant difference in risks for fatal bleeding and symptomatic intracranial hemorrhage, even when present, is difficult to show. Additionally, many reviews do not separate these endpoints from overall mortality and major bleeding. Consequently, authors should include all available observational, population-based, and/or case-control risk assessment studies to adequately evaluate safety.

Example #24 (Table 1): Anticoagulants versus antiplatelet therapy for preventing stroke in patients with NRAF and a history of stroke or transient ischemic attack.[39] For patients who have NRAF and a history of stroke, this review, which included only 2 small RCTs of relatively young patients taking warfarin vs aspirin (971 patient-years of follow-up with warfarin), is used to justify warfarin for secondary stroke prevention. Intracranial bleeding developed in 4 of 971 patient-years (0.4% per year) of the warfarin-treated patients vs 2 of 990 (0.2% per year) of NSAID-treated patients (P = not significant). However, in observational studies, the reported yearly rates (0.46%[40], 0.62%[41], 1.26%[42], 2.5%[43]) of intracranial bleeding suggest a higher incidence in general clinical practice. The study with the highest yearly intracranial bleeding rate, 2.5%,[43] followed NRAF patients older than 65 years and was the only study to follow patients from the onset of anticoagulation. This may be more representative, because most NRAF patients are older than 65 years and the bleeding rate in the initial month of treatment is 10 times the monthly rate after the first year.[44]

7. The primary endpoint, which determines the main conclusions of the review, is a surrogate rather than a clinical endpoint.

A surrogate endpoint is a test (eg, venogram, Doppler ultrasonography, or lung scan). A clinical endpoint matters to patients (eg, death, stroke, heart attack, or major hemorrhage). Government drug regulatory agencies generally but not always maintain that clinical endpoints rather than surrogate measures should be the basis of conclusions from analyses of RCTs in the context of drafting clinical guidelines.

Example #5 (Table 1): Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment.[45] A review that included only one RCT had a primary endpoint of occlusion or restenosis greater than 50% shown by duplex sonography or angiography (a surrogate endpoint). The secondary endpoints, amputation, death, MI, stroke, major bleeding, and side effects, were the important clinical outcomes.

The authors concluded, “The use of low molecular weight heparins might be superior to unfractionated heparin to prevent early and mid-term reocclusion/restenosis after femoropopliteal angioplasty.”

However, UH increases bleeding but does not reduce adverse clinical events compared with dextrose.[46] LMWH is not better than UH with regard to preventing amputation, the only clinical endpoint reported (LMWH, 3/86; UH, 3/86).[45] Since both LMWH and UH cause high rates of bleeding and are not found to be efficacious in reducing clinical adverse outcomes related to thrombosis, their use should be reassessed.

8. The primary endpoint, which determines the main conclusions of the review, should also include safety endpoints rather than just efficacy endpoints.

Major bleeding is as important as or more important than recurrent VTE or nonfatal MI as a clinical endpoint. Consequently, instead of symptomatic thrombosis (eg, recurrent VTE or MI) as the only primary outcome measure, the primary endpoint of anticoagulant studies should be some combination of symptomatic thrombosis and major bleeding.

Example #42 (Table 1): Interventions for preventing VTE following abdominal aortic surgery.[47] The 2 primary outcomes in this meta-analysis were the incidence of DVT (symptomatic and asymptomatic) and PE (symptomatic and asymptomatic). Secondary outcomes were all-cause mortality and adverse events, including major and minor bleeding. Asymptomatic DVT and PE (surrogate endpoints) are irrelevant, because there is no evidence that asymptomatic VTE correlates with clinically important outcomes. The clinically relevant composite primary outcome should be symptomatic VTE and major bleeding.

Indeed, in the 147 participants included in the 2 RCTs of this review, there were no deaths from VTE in either group but there were 8 major bleeding episodes in the group receiving heparin, two of which were fatal. The Cochrane authors concluded, “There was insufficient available evidence to justify the use of anticoagulant prophylaxis in aortic operations” and recommended more anticoagulation research. However, the safety and efficacy evidence from this review considered together strongly suggests that further experimentation with anticoagulation after abdominal aortic aneurysm surgery should be discouraged.

9. Fatal bleeding and/or intracranial bleeding were not (for protocols will not be) included in the primary or secondary endpoints.

Major hemorrhage is generally defined as any fatal bleeding episode; intracranial hemorrhage; or bleeding severe enough to require transfusion, operation, or a prolonged hospital stay. Most Cochrane anticoagulation reviews do not separately report intracranial bleeding and fatal hemorrhage. This should be done because of the particular importance of these terrible outcomes to patients and clinicians.

Example #9 (Table 1): Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures.[16] While the comparisons of heparin and LMWHs in this review included mortality and wound hematomas, they did not include fatal bleeding or intracranial hemorrhage. The risk for these complications with heparin or LMWH is unknown, and the authors do not claim that there are clear benefits in reducing symptomatic clotting. If even 1% of patients had fatal bleeding or symptomatic intracranial bleeding, there would be no justification for further trials with anticoagulants for hip fracture patients.

10. Conclusions of the review were based on data from RCTs of patients that are not representative of patients in general clinical practice.

Younger, more compliant, and healthier persons will have better results in anticoagulant trials than people at high risk for bleeding or those who may not reliably return for monitoring of treatment.

Example #43 (Table 1): Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonvalvular atrial fibrillation and no history of stroke or transient ischemic attacks.[48] Patients selected for the RCTs in this Cochrane review were significantly younger and probably more reliable than a general sample of patients with atrial fibrillation. Of all patients with NRAF treated in the institutions involved in the RCTs of this meta-analysis, only 3% to 40% were entered into the trials. For instance, the RCT ACTIVE W enrolled about 2 of 3 participants included in the meta-analysis. ACTIVE W excluded anyone older than 79 years.[49] A population-based study in Cincinnati illustrates the importance of age. It found that anticoagulation associated intracranial hemorrhage occurred in 4.4 people per 100,000 overall and 45.2 per 100,000 people older than 79 years.[50] In the Implications for Practice section from this review, the recommendation for VKA prophylaxis in high-risk NRAF patients did not specify any age restrictions.

11. A patented, expensive treatment, which is not the subject of the review and is not evidence-based to work, is endorsed in the Implications for Practice section.

Example #6 (Table 1): Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery.[51] The Implications for Practice section of this review stated, “A combination of ASA and a thienopyridine, e.g. clopidogrel, might be as effective for primary patency rates as vitamin K antagonists.” However, no RCTs of clopidogrel or other thienopyridine were described in this Cochrane review. Consequently, this non-evidence-based endorsement for a patented, expensive drug is inappropriate.

12. The review is not updated to include crucial recent RCT(s) or other data.

Cochrane reviews are supposed to be kept up to date by the timely addition of relevant new trials or other information.

Example #33 (Table 1): Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischemic attack or minor stroke of presumed arterial origin.[52] At the time of publication of this review of RCTs (July 2006), 3 RCTs were said to be ongoing and the Cochrane authors recommended continuing recruitment. However, in 2005, before this Cochrane review was published, the Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) trial was terminated early because of the high incidence of death in the warfarin group (4.3% in the aspirin group vs 9.7% in the warfarin group [RR, 0.46; 95% CI, 0.23–0.90; P = .02]).[53] The authors concluded, “Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.” In June 2006, the Aspirin Versus Anticoagulants in Symptomatic Intracranial Stenosis (AVASIS) trial concluded: “Our study suggests that aspirin is the treatment of choice for the prevention of vascular events in patients with symptomatic middle cerebral artery stenosis.”[54,55] In February 2007, an RCT comparing medium-intensity oral anticoagulants with aspirin after cerebral ischemia of arterial origin echoed the same result.[56] This Cochrane review should be updated to indicate that VKAs should be contraindicated in acute ischemic stroke and that further anticoagulant trials in people with past transient ischemic attacks or minor strokes would be unethical.

13. Biases exist in the selection of trials for inclusion in the review.

Frequently, potentially eligible RCTs are excluded from Cochrane anticoagulation meta-analyses for a variety of legitimate reasons. However, some reviews have selection biases that demonstrably affect the conclusions of the review.

Example #44 (Table 1): Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.[10] In this review of RCTs comparing heparin with placebo for prolonging survival in patients with cancer who have no other indication for anticoagulation, the major conclusions of the review depend on the statistically significant mortality benefit – favorable to heparin – reported in the 2004 FAMOUS RCT led by Kakkar and associates.[57] Kakkar was also a coauthor of one of the 7 review-eligible studies for which data were not available.[58] In all, 12 RCTs were eligible but only 5 were included. Consequently, a potential bias in the inclusion of trials, based on selective availability of data from RCT authors, makes the conclusions of this review, favorable to anticoagulants, questionable.

The biases and errors in clinical trial data described in this review call into question the efficacy of anticoagulants for the 30 indications for anticoagulants listed in Table 3.

Table 3.

Questionable Indications for Anticoagulants

	Indication	Associated Cochrane Review(s)
1	Treatment of VTE	#1
2	Prevention of restenosis/reocclusion following peripheral endovascular treatment	#5
3	Prevention of VTE in patients with lower leg immobilization	#3
4	Preventing deep venous thrombosis and pulmonary embolism following surgery for hip fractures	#9 and #11
5	Prevention of VTE in general medical patients	#10
6	Prevention of VTE following total hip	#11 and #39
7	Prevention of VTE following knee replacement	#11 and #39
8	Treatment of acute ischemic stroke	#13, #14, #15, and #17
9	Prevention of recurrence following presumed noncardioembolic ischemic stroke or transient ischemic attack	#16 and #33
10	Treatment of heart failure in sinus rhythm	#18 and #19
11	Treatment of intermittent claudication	#21
12	Prolonging survival in patients with cancer who have no other indication for anticoagulation (oral anticoagulation)	#22
13	Prolonging survival in patients with cancer who have no other indication for anticoagulation (parenteral anticoagulation)	#44
14	Prevention of stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack	#23, #24, #33, and #42
15	Prevention of VTE in pregnancy and the early postnatal period	#26
16	Treatment of acquired or inherited thrombophilias in pregnant women	#27
17	Prevention of VTE after colorectal surgery	#28
18	Treatment of acute coronary syndromes	#29 and #30
19	Treatment of ST-segment elevation myocardial infarction	#31
20	Treatment of recurrent pregnancy loss in women without the antiphospholipid syndrome	#34
21	Secondary prevention of thrombosis complications in coronary heart disease	#35
22	Prevention of VTE in adults undergoing knee arthroscopy	#38
23	Prolonging the patency of central venous catheters in children (heparin-bonded catheters)	#40
24	Prevention of central venous catheterization-related thrombosis in children (low molecular weight heparin)	#41
25	Prevention of VTE following abdominal aortic surgery	#42
26	Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant	#37, #45
27	Prevention of thromboses in patients with prosthetic heart valves	#46
28	Treatment of carotid artery dissection	#47
29	Prevention of thrombosis after coronary stenting	#50
30	Treatment of cerebral sinus thrombosis	#37

VTE = venous thromboembolism

Discussion

The strength of this review is that it systematically analyzed all of the Cochrane anticoagulation reviews and protocols from the standpoint of evidence-based medicine. The limitation is that the authors of only 13 of the 57 eligible Cochrane reviews and protocols replied to the feedback letters, and the Cochrane disputes editor has not yet responded to my complaint about the peer reviewing of the review I coauthored. In the 13 replies I did receive, several authors agreed with some or all of my points (Table 1).

From 1999 to 2004, worldwide sales of antithrombotic drugs grew by 18% per year to $650 million for VKAs and $3.6 billion for heparins. About half of these drugs were sold in the United States,[59] so estimates of worldwide complications due to anticoagulants would be at least twice the number in the United States, given the lower costs of these drugs elsewhere. The total expense of these drugs extends far beyond the cost of the medication itself (eg, diagnostic tests, hospitalization, monitoring, drug administration, treatment of complications).

In 2004, 31 million prescriptions (typically for a 1-month supply) were written for warfarin in the United States,[60] so about 2.6 million people in the United States took this medication each day (31 million/12 months = 2.6 million). Based on the yearly rate of anticoagulation-associated intracerebral hemorrhage (AAICH) reported in warfarin treatment observational studies (0.46%,[40] 0.62%,[41] 1.26%,[42] and 2.5%[43]) and 1 population-based study (0.67%[50]), 12,000 to 65,000 cases of this type of hemorrhage were caused by warfarin in 2004 in the United States. A meta-analysis of prospective research studies shows that 0.6% to 0.8% of RCT patients treated with VKAs have fatal hemorrhage each year.[44,61] In nonresearch outpatient settings, risk for fatal bleeding with VKAs is probably higher (eg, 2%/yr[42] and 1%/yr[62]). Given the number of people receiving VKAs in the United States (2.6 million) and the range of fatal hemorrhage rates reported (0.6%-2.0%), between 15,000 to 52,000 experience fatal bleeding due to VKAs in the United States alone.

Full-dose heparin is given for treatment of VTE, ACSs, open-heart surgery, and percutaneous coronary interventions. Between 160,000 to 600,000 Americans each year receive full-dose heparin or LMWH for VTE treatment.[2] The American Heart Association estimates that 2.7 million residents of the United states have ACS, open heart surgery, or percutaneous coronary interventions each year.[63]

Based on a systematic literature review, the average daily frequencies of fatal, major, and total bleeding during full-dose heparin therapy for VTE were 0.05%, 0.8%, and 2.0%, respectively.[44] Petersen and colleagues[64] reported the daily rate of major bleeding due to heparin or LMWH for ACSs as 0.66%. Consequently, for approximately 3 million full-dose heparin courses (average 7 days) in the United States, about 138,000 to 168,000 people will have major bleeding (3 million people × 0.0066 to 0.008 major bleed risk/day × 7 days = 138,000–168,000) and 10,500 will die of hemorrhage (3 million people × 0.0005 fatal bleed risk/day × 7 days = 10,500).

Among other anticoagulants, low-dose heparin and LMWH are used for VTE prophylaxis. A review of 52 RCTs that studied VTE anticoagulant prophylaxis (n = 33,813) showed that low-dose heparins approximately doubled the rates of hemorrhage, including major bleeding of the gastrointestinal tract (26/12,928 = 0.2%) and retroperitoneum (10/12,642 = 0.08%).[65] Fatal and intracranial bleeding were not reported. Based on these data, for the 6 million people given low-dose heparin or LMWH each year for VTE prophylaxis in the United States,[66,67] about 8400 will develop anticoagulant-related major bleeding.

While major bleeding is a definite risk with low-dose heparin in VTE prophylaxis, rebound hypercoagulability is possibly an even greater risk. To estimate the risk, consider that about 12 million of the 38 million persons (32%) hospitalized in the United States per year have indications for prophylactic anticoagulants and about 6 million (50%) of those at high risk receive anticoagulant prophylaxis.[66,67] Application of the results of the Goldhaber chart review study[37] for rebound hypercoagulability risk for fatal PE shows that out of 80,000 hospital discharges, about 25,600 (32%) would have high risk for hospital-acquired VTE. Of those at high VTE risk, about half (12,800) would receive anticoagulant prophylaxis. Consequently, fatal PE occurred in 1 out of an estimated 12,800 cases in high-risk patients who did not receive anticoagulation vs 12 of 12,800 who did receive anticoagulant prophylaxis (using the estimated OR, 12.0; 95% CI, 1.6–92 – see example 5 from “Categories of Methodological Errors and Biases”). In other words, about 700 to 40,000 people die each year in the United States of rebound hypercoagulation caused by prophylactic anticoagulation (6,000,000 hospitalized people/yr with anticoagulant prophylaxis × 11/12,800 [excess risk for fatal PE per Goldhaber study] = 5156; 95% CI, 688–39,531).

If anticoagulants are not efficacious in preventing symptomatic and fatal clotting for the 30 indications in Table 3, then at least 50,000 bleeding deaths (ie, 15,000 due to VKAs plus 10,500 due to heparins and at least twice that number worldwide) occur each year. We might also avoid the tens of billions of dollars that anticoagulation costs in diagnostic tests, drugs, monitoring, and treatment of complications.

The findings of this review do not imply that clinical practice regarding the use of anticoagulant drugs for any indications should be immediately changed. These findings first need to be transparently and publicly critiqued by unbiased government and academic experts in evidence-based medicine.

Conclusion

The efficacy and safety of anticoagulant drugs for 30 government regulatory agency approved and off-label indications are in question. At a minimum, 50,000 people have fatal bleeding episodes each year worldwide due to anticoagulant treatment or prophylaxis for these indications. An objective, transparent reassessment of the evidence base of all indications for anticoagulant use (regulatory agency approved and off label) should be carefully done by the government regulatory agencies, including the FDA in the United States and the The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom.

Glossary

Abbreviation Notes

ACS

acute coronary syndrome

ASA

acetylsalicylic acid (aspirin)

CI

confidence interval

DVT

deep venous thrombosis

FDA

US Food and Drug Administration

HIT

heparin-induced thrombocytopenia

HITT

heparin-induced thrombocytopenia with thrombosis

LMWH

low-molecular-weight heparin

MI

myocardial infarction (heart attack)

NRAF

nonrheumatic atrial fibrillation

NSAID

nonsteroidal anti-inflammatory drug

NVAF

nonvalvular atrial fibrillation

OR

odds ratio

PE

pulmonary embolism

RCT

randomized, controlled trial

RR

risk ratio

UH

unfractionated heparin

VKA

vitamin K antagonists (or vitamin K inhibitors)

VTE

venous thromboembolism (DVT and PE).