Most of the studies in the literature propagate that the incidence of frozen shoulder is higher in people with diabetes. According to the American Diabetic Association, the average age of people with frozen shoulder is 52 years. Among people 40 and over, the condition affects 2 to 4 percent of the general population and up to 25 percent of people with diabetes. But no definite pathophysiological mechanism to support the data has been postulated.
Several questions remain unanswered.
Do people with diabetes experience worse outcomes from frozen shoulders than those without diabetes?
Does uncontrolled diabetes have a higher risk or severity of disease?
Do people with diabetes develop frozen shoulder at an earlier age than non-diabetics?
Does Diabetes delay the recovery from a frozen shoulder?
Answers to the above questions may be yes in several studies in scientific literature. However, the certainty in evidence in most such studies is moderate to low. In our experience of more than 30 years, we also don't find any such correlation.
Frozen shoulder undoubtedly has a higher incidence among patients with Myocardial Infarction, but the incidence, duration of disability, severity of symptoms, and age of onset are not remarkably different from the general population.
Most of the studies in the literature propagate that the incidence of frozen shoulder is higher in people with diabetes. According to the American Diabetic Association, the average age of people with frozen shoulder is 52 years. Among people 40 and over, the condition affects 2 to 4 percent of the general population and up to 25 percent of people with diabetes. But no definite pathophysiological mechanism to support the data has been postulated.
Several questions remain unanswered.
Do people with diabetes experience worse outcomes from frozen shoulders than those without diabetes?
Does uncontrolled diabetes have a higher risk or severity of disease?
Do people with diabetes develop frozen shoulder at an earlier age than non-diabetics?
Does Diabetes delay the recovery from a frozen shoulder?
Answers to the above questions may be yes in several studies in scientific literature. However, the certainty in evidence in most such studies is moderate to low. In our experience of more than 30 years, we also don't find any such correlation.
Frozen shoulder undoubtedly has a higher incidence among patients with Myocardial Infarction, but the incidence, duration of disability, severity of symptoms, and age of onset are not remarkably different from the general population.
This research by Mooghali and team provide valuable and disturbing data on the problem of financial conflicts of interest (COI) in clinical practice guidelines.(1) Failure of authors and committee members to accurately disclose potential COI raises concerns about lack of transparency in the process, bias in the resulting guidelines, and ultimately harm to patients.
The pioneering work in this area was done by the American Academy of Family Physicians, which published in 1994 the first international call for an explicit declaration of conflicts of interest in the development of clinical practice guidelines.(2) This has been followed by policies on COI by other groups of primary care physicians in the US(3,4), the UK(5,6) and Canada(7,8).
Primary care physicians have been early champions of evidence-based medicine and explicit clinical practice guidelines. They are also the clinicians working at the point of care, partnering with patients to make shared decisions. The best in care requires the best guidance based on the best evidence. Therefore, potential COIs must be fully disclosed and critically managed by all involved in producing, disseminating, and implementing clinical practice guidelines.
REFERENCES
1.Mooghali M, Glick L, Ramachandran R, et al. Financial conflicts of interest among US physician authors of 2020 clinical practice guidelines: a cross- sectional study. BMJ Open 2023;13:e069115. doi:10.1136/ bmjopen-2022-069115
2. Phillips...
This research by Mooghali and team provide valuable and disturbing data on the problem of financial conflicts of interest (COI) in clinical practice guidelines.(1) Failure of authors and committee members to accurately disclose potential COI raises concerns about lack of transparency in the process, bias in the resulting guidelines, and ultimately harm to patients.
The pioneering work in this area was done by the American Academy of Family Physicians, which published in 1994 the first international call for an explicit declaration of conflicts of interest in the development of clinical practice guidelines.(2) This has been followed by policies on COI by other groups of primary care physicians in the US(3,4), the UK(5,6) and Canada(7,8).
Primary care physicians have been early champions of evidence-based medicine and explicit clinical practice guidelines. They are also the clinicians working at the point of care, partnering with patients to make shared decisions. The best in care requires the best guidance based on the best evidence. Therefore, potential COIs must be fully disclosed and critically managed by all involved in producing, disseminating, and implementing clinical practice guidelines.
REFERENCES
1.Mooghali M, Glick L, Ramachandran R, et al. Financial conflicts of interest among US physician authors of 2020 clinical practice guidelines: a cross- sectional study. BMJ Open 2023;13:e069115. doi:10.1136/ bmjopen-2022-069115
2. Phillips WR. Clinical policies: making conflicts of interest explicit. JAMA 1994; 272(19):1479. doi:10.1001/jama.1994.03520190021010
3. Schünemann HJ, Al-Ansary LA, Forland F, Kersten S, Komulainen J, Kopp IB, et al. Guidelines International Network: Principles for disclosure of interests and management of conflicts in guidelines. Ann Intern Med. 2015;163:548-553. doi:10.7326/M14-1885Ann Int Med 2016
4. Phillips WR. American Academy of Family Physicians pioneered full disclosure in clinical
guidelines. (eLetter 7 January) Ann Intern Med. 2015;163:548-553. doi:10.7326/M14-1885Ann Int Med 2016
5. Moore, Ainsley, et al. Financial conflict of interest among clinical practice guideline-producing organisations. British J General Practice 70.700 (2020): 530-531. Web. 30 Oct. 2020. doi: 10.3399/bjgp20X713177
6. Phillips WR. General practice leads in transparency of clinical guidelines. (eLetter 30 OPct 2020) British J General Practice 70.700 (2020): 530-531. https://bjgp.org/content/70/700/530/tab-e-letters
7. Allan GM, Cauchon M, Katz A, Kuling PJ, Moore S, Scrimshaw C, Stalker P. Endorsement of clinical practice guidelines. Criteria from the College of Family Physicians of Canada. Can Fam Physician 2021;67:499-502. doi: 10.46747/cfp.6707499
hi-
This seems like a really interesting, and potentially very important study. I'm concerned though that you are not listing as a primary objective improving the CD4/CD8 ratio. While a home run could be decreasing the reservoir, whether you decrease the reservoir or not, you might improve the ratio and this by itself could alter future cancer susceptibility (anal, colon, lung) and may avoid zoster, or tb acquisition (if in India for example) and could improve immune response to vaccines. I'm not saying all of this naturally follows, but if you beat down CMV it is at least as likely that you make the immune system less distracted then it is you decrease the reservoir. Thanks for getting this together though and I look forward to the outcomes. Rob Striker UW Madison
While I agree with the conclusion of this research that it is necessary for the government to communicate uncertainties with the general public about public health and vaccination specifically in the COVID-19 era, I’m afraid that data of the present study was not able to support this conclusion.
In the emotions part of the result section, the authors reported that no significant between group differences of uncertainty was found in any circumstances, neither after receiving the announcement (p = .091), nor after reading the conflicting information (p = .462), or overall (p = .628). This result indicated that the intervention of the present study failed to manipulate different level of certainty between two intervention groups. All analysis and the corresponding results based on condition as independent variable tended to be invalid because it didn’t pass the manipulation check.
Under this circumstance, the level of uncertainty before intervention would be a more reasonable choice as the primary independent variable. The similar mediation model in the present study was tested with the level of uncertainty before intervention as independent variable and the vaccination intention after intervention as dependent variable. If trust in government representative and perceived vaccine effectiveness before intervention were tested as mediators in the model, indirect effects of both path were significant, with the trust path β = -0.0898, 95% CI = [-0.1401, -0.0426], and...
While I agree with the conclusion of this research that it is necessary for the government to communicate uncertainties with the general public about public health and vaccination specifically in the COVID-19 era, I’m afraid that data of the present study was not able to support this conclusion.
In the emotions part of the result section, the authors reported that no significant between group differences of uncertainty was found in any circumstances, neither after receiving the announcement (p = .091), nor after reading the conflicting information (p = .462), or overall (p = .628). This result indicated that the intervention of the present study failed to manipulate different level of certainty between two intervention groups. All analysis and the corresponding results based on condition as independent variable tended to be invalid because it didn’t pass the manipulation check.
Under this circumstance, the level of uncertainty before intervention would be a more reasonable choice as the primary independent variable. The similar mediation model in the present study was tested with the level of uncertainty before intervention as independent variable and the vaccination intention after intervention as dependent variable. If trust in government representative and perceived vaccine effectiveness before intervention were tested as mediators in the model, indirect effects of both path were significant, with the trust path β = -0.0898, 95% CI = [-0.1401, -0.0426], and the effectiveness path β = -0.1444, 95% CI = [-0.2059, -0.0926]. The total effect from uncertainty to vaccine intention was β = -0.5804, 95% CI = [-0.6686, -0.4921], and the direct effect was β = -0.3591, 95% CI = [-0.4593, -0.2484]. This new mediation model indicated that higher level of uncertainty would lead to less intention for vaccination, this effect was mediated by trust in government representative and perceived vaccine effectiveness.
Changing the independent variable from condition to the level of uncertainty before intervention led to the opposite conclusion of the present study. This suggested that the conclusion of the present study was at least not robust.
We thank Dr. Guijarro for his comments (1) and are pleased to respond to his main concerns on our article. He states that “the claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non-cardiovascular mortality”. However, we should bear in mind that both total and cardiovascular mortality were numerically increased in the evolocumab group compared to placebo, which is inconsistent with a significant reduction in cardiovascular events. Additionally, this drug is indicated for patients with previous cardiovascular disease. If potential cardiac harm were confirmed, additional concerns with evolocumab in this population would be reasonably expected.
We acknowledge that “none of our concerns is supported by any statistically significant difference”. However, since cardiovascular mortality is included in the composite primary endpoint, an exaggerated assessment of cardiovascular mortality could have contributed to inappropriate early termination of the trial ‘for benefit’. If the point estimate we identified of a 20% relative risk increase in cardiovascular mortality were maintained, the non-significant increase from evolocumab might have reached statistical significance before the end of the prespecified 56-month follow-up.
Dr. Guijarro also mentions that “the FOURIER open label extension study suggests that longer treatment with evolocumab may indeed reduce cardiovascular mortality”(2). However, the results of this study di...
We thank Dr. Guijarro for his comments (1) and are pleased to respond to his main concerns on our article. He states that “the claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non-cardiovascular mortality”. However, we should bear in mind that both total and cardiovascular mortality were numerically increased in the evolocumab group compared to placebo, which is inconsistent with a significant reduction in cardiovascular events. Additionally, this drug is indicated for patients with previous cardiovascular disease. If potential cardiac harm were confirmed, additional concerns with evolocumab in this population would be reasonably expected.
We acknowledge that “none of our concerns is supported by any statistically significant difference”. However, since cardiovascular mortality is included in the composite primary endpoint, an exaggerated assessment of cardiovascular mortality could have contributed to inappropriate early termination of the trial ‘for benefit’. If the point estimate we identified of a 20% relative risk increase in cardiovascular mortality were maintained, the non-significant increase from evolocumab might have reached statistical significance before the end of the prespecified 56-month follow-up.
Dr. Guijarro also mentions that “the FOURIER open label extension study suggests that longer treatment with evolocumab may indeed reduce cardiovascular mortality”(2). However, the results of this study differ to a great extent from those in the parent FOURIER trial. This may be related to the methodological limitations of open trials. Furthermore, a systematic review based on the results published at ClinicalTrials.gov shows that evolocumab probably increases the risk of all-cause mortality compared to placebo (OR 1.12; 95% CI 1.00-1.25) (3).
Dr. Guijarro also states that “no one disputes its favourable effects not simply on lipid levels, but in cardiovascular event reduction in patients with established atherosclerotic cardiovascular disease”. We respectfully disagree on this aspect, since the aim of the FOURIER trial was precisely to shed light on the cardiovascular effects of evolocumab. Once the trial had started, the manufacturer amended the protocol in order to split cardiovascular events into two categories, namely, “efficacy” and “safety” outcomes. For those included as “efficacy” outcomes, no narratives are available in the Clinical Study Report (CSR), whereas information on cardiovascular events labelled as “adverse events” (safety outcomes) was given. The proportion of patients with at least one cardiac event in the evolocumab group was 13.7% (1885/13769) vs 14.2% (1948/13756) in the placebo group. No statistically significant differences were observed between groups, RR 1.03 (95%CI, 0.98 to 1.10) (CSR report body part 1, page 1197 of 5092). The lack of efficacy of evolocumab in the prevention of cardiac events labelled as “safety” outcomes is not consistent with the reported efficacy in the reduction of the incidence of cardiac events labelled as “efficacy” outcomes in the NEJM 2017 publication. Since Dr. Guijarro thinks that “it is worth carefully reviewing the adjudication of cardiovascular mortality”, he may share our conclusion that independent review of the adjudication of efficacy endpoints is also desirable. For this, we need companies and regulators to be more transparent and provide full access to the trial’s information.
Additionally, Dr Guijarro states that “the higher the extension of cardiovascular disease, the higher the potential absolute benefit of PCSK9 inhibition therapy”. This statement is based on the Recommendations of the Spanish Society of Arteriosclerosis (4). In this document, authors acknowledge that recommendations for patients with more than two uncontrolled additional risk factors are rather weak, with a “low” level of evidence (page 137 in the Journal article). In the FOURIER trial, patients with prior myocardial infarction experienced no benefit of evolocumab vs placebo in the primary endpoint after one year follow-up (CSR report body part 1, page 125 of 5092). This is inconsistent with the belief that people with more severe coronary artery disease will obtain a greater benefit from the drug.
Finally, Dr. Guijarro states that “we should ask ourselves why so many atherosclerotic patients with uncontrolled LDL cholesterol levels are not receiving adequate lipid-lowering therapy, including PCSK9 Inhibitors if required”. However, we think that we and others, should first ask, after evolucumab reduced LDL-c levels so dramatically in the FOURIER trial, why did it show no reduction in mortality, and why benefits assessed as a reduction of cardiovascular events were so small, if real.
References
(1) Erviti J, Wright J, Bassett K, et al. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data. BMJ Open 2022;12:e060172. doi:10.1136/bmjopen-2021-060172
(2) O’Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease. Circulation 2022;146:1109–19. doi:10.1161/CIRCULATIONAHA.122.061620
(3) van Bruggen FH, Nijhuis GBJ, Zuidema SU, Luijendijk H. Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review. Expert Rev Clin Pharmacol. 2020 Jul;13(7):787-796. doi: 10.1080/17512433.2020.1787832. Epub 2020 Jul 13. PMID: 32597252.
(4) Ascaso JF, Civeira F, Guijarro C, et al. Indications of PCSK9 inhibitors in clinical practice. Recommendations of the Spanish Society of Arteriosclerosis (SEA), 2019. Clin Investig Arterioscler 2019;31:128–39. doi:10.1016/j.arteri.2019.04.002
Intramuscular (i.m.) ChAdOx1 nCOV19 , trade name "covishield " vaccine of company astrazeneca and sub licensed with Serum Institute of India ( mRNA 1273 vaccine for Spike Protein /RBD) and of Bharat Biotech company's whole virion inactivated Vero cell "co vaccine" which were given to Indian population in two minimum doses( free of cost) , in India ,were remarkably effective in preventing severe COVID-19 pneumonia, ARDS and hospitalisation with all sub variants( VOC) of omicron variants of concern of SARS COV-2 ,those were circulated so far in India since 2021 March and their full dose ( two/ or precautionary 3rd doses in 27% Indians ) use being associated with declining hospitalisation , ARDS, ventilation and COVID 19 related death . However, current vaccines those are given by the Indian government's health department can provide only transient protection against respiratory SARS- COV -2 viral replications , onward transmission and continuing emergence of variants of concern, by contrast, respiratory infection with SARS-CoV-2 could induces more potent serum IGg and IGa antibody mediated ( against spike protein and RBD protein) immunity against breakthrough infections ( re- infection even after vaccination or after clinical or subclinical infection) , mucosal immune defences that could inhibit viral replication and transmission, but did not happened it so in real world . Although covishield/ or co vaccine i.m. vaccinations transi...
Intramuscular (i.m.) ChAdOx1 nCOV19 , trade name "covishield " vaccine of company astrazeneca and sub licensed with Serum Institute of India ( mRNA 1273 vaccine for Spike Protein /RBD) and of Bharat Biotech company's whole virion inactivated Vero cell "co vaccine" which were given to Indian population in two minimum doses( free of cost) , in India ,were remarkably effective in preventing severe COVID-19 pneumonia, ARDS and hospitalisation with all sub variants( VOC) of omicron variants of concern of SARS COV-2 ,those were circulated so far in India since 2021 March and their full dose ( two/ or precautionary 3rd doses in 27% Indians ) use being associated with declining hospitalisation , ARDS, ventilation and COVID 19 related death . However, current vaccines those are given by the Indian government's health department can provide only transient protection against respiratory SARS- COV -2 viral replications , onward transmission and continuing emergence of variants of concern, by contrast, respiratory infection with SARS-CoV-2 could induces more potent serum IGg and IGa antibody mediated ( against spike protein and RBD protein) immunity against breakthrough infections ( re- infection even after vaccination or after clinical or subclinical infection) , mucosal immune defences that could inhibit viral replication and transmission, but did not happened it so in real world . Although covishield/ or co vaccine i.m. vaccinations transiently could reduce viral transmission, vaccines with if breakthrough infections occurred showed peak nasopharyngeal viral loads similar to those in unvaccinated individuals (1,2 ).
One study, showed that viral loads declined more rapidly in vaccines with neutralising plasma antibodies ( 2 ) but it is not yet clear whether this effect is also mediated by passive transudation of plasma antibody IGa into the nasal or other naso pharyngial respiratory mucosa, or whether intra muscular COVID- 19 vaccination can also elicit nasal mucosal responses primed by infection (as it is observed after i.m. influenza vaccination following an intranasal priming).
Vaccine with covisheld or covaccine that induces serum IGa and IGg are mostly monomeric in nature and these antibodies are produced in the bone marrow, whereas nasal IGg and IGa are polymeric and they are produced locally by mucosal plasma cells. We all know that the polymeric nasal IGa , the antibody that plays very important role for neutralisation of any virus in the upper respiratory tract, and so passive transudation of plasma antibody if at all into the nasal mucosa is unlikely to provide long durable sterilising immunity (3).So understanding whether i.m. vaccination after COVID-19 can at all recall nasal IGa responses is an important step towards market development of nasal vaccines for SARS- COV-2 which can prevent infection and transmission of the virus .
During worldwide circulation of SARS-CoV-2,from 2019 onward to till date multiple successive variants of concern (VOC) has genetically mutated,and emerged with high and higher Ro in the community transmission as well as immune evasion or vaccine escape phenomenon, resulting in breakthrough infection even to vaccinated people worldwide including in India also . Some Omicron sub variants appeared that are less susceptible to vaccine-induced immunity and showed high reinfection rates like B 5.2.1.7 VOC as in China, Japan , USA.but not in India ( The real data from china usually not found ) . In India, immunity is obtained to a large percentage of people by successive subclinical or clinical omicron infections and minimum two doses vaccination programs possibly provided and will provide superior protection against Omicron compared with either alone . vaccination regimes which combined both intra nasal and i.m. administration in mice induced enhanced mucosal protection against SARS-CoV-2 variants (4) .This suggests that first priming the nasal mucosa with infection or by i.m vaccine is required to induce effective intra nasal local antibody responses that may provide enhanced immunity against current and future variants. However, the cross-reactivity of nasal antibodies after infection with pre-Omicron virus is unknown.
It is seen that commonly nasal virus-specific IGA levels also fell back to pre-COVID levels after 3 to 9 months and Omicron-binding nasal responses were particularly short-lived one .Nasal IGa responses are compartmentalised from systemic responses after vaccination, which boosted nasal and plasma IGg but had limited effects on nasal IGA.The durability of nasal antibody responses has hitherto been unclear. A Dutch study with healthcare workers found that nasal antibodies lasted maximum for 9 months after mild infection, others demonstrated rapid waning even after 3 months ( 5,6) . Neither study examined a large cohort of hospitalised patients, and findings confirm that COVID-19 can induce durable mucosal immunity. Average, nasal IGa responses disappear after 9 months and Omicron-binding IGa is particularly short-lived. Nasal IGa is the most abundant mucosal antibody and provides an important first-line defence against respiratory infection. What this author want to say is that i.m. vaccination can also boost nasal IgG, but it has limited effects on IgA, that i.m vaccination only transiently boosts nasal IgA. mRNA vaccines tend to induce stronger circulating antibody responses than those using adenoviral vectors, but this may not apply to nasal responses. Taken together this author suggest that i.m. vaccination after COVID-19 is unlikely to recall mucosal responses, and nasal IgA responses, especially those to Omicron, are more short-lived and are not substantially affected by vaccination. There is lack of long-term sterilising immunity after previous infection and/or vaccination and it highlight the need for mucosal vaccines that target nasal IgA responses. By enhancing nasal antibody responses, mucosal vaccines might prevent infection and transmission more effectively, enabling greater control of the pandemic and limiting the emergence of variants.
Bharat Biotech's intranasal Covid vaccine named "Incovacc " received Indian government approval for use as a booster dose in India the country-wide mass inoculation program. It will be administered to those above 18 years old who have previous two doses of covishield or co vaccine as a booster dose and will be first made available in all private hospitals with purchase price by minimum money Rs 800/ per dose in private hospitals of India
( i.e. Rs 1600/ for 8 nasal drop doses 4 drops in each nostril ) and Rs 300/ ( 8 nasal drops costs government 600/ ) in government rate- A good method of huge profitable business in the name of covid- 19 omicron sub VOC . It will also be available on CoWIN app . Few weeks back on 1st December 2022, it had got approval from the Central Drugs Standard Control Organisation( CDSCO) for restricted use in emergency situations in the age group of 18 and above. The government in a release on December 1 had called it "World’s first intranasal covid vaccine. Bharat Biotech ,"Incovacc " is a "recombinant replication deficient adenovirus vectored vaccine with a pre-fusion stabilised spike protein." It stimulates a broad immune response – neutralising IgG, mucosal IgA, and T cell responses( ??), it says. It also triggers immune responses at the site of infection (in the nasal mucosa) – essential for blocking both infection and transmission of Covid-19. Phase 3 clinical trial done in 3000 participants, Incovacc has been shown to generate good immunity following 2 doses given 4 weeks apart.Headache, Fever, Running nose, Sneezing were reported as likely side effects, while severe allergic reaction was said to be "rare."
References
1).Eyre D.W. Taylor D. Purver M. et al.
Effect of covid-19 vaccination on transmission of alpha and delta variants.
N Engl J Med. 2022; 386: 744-756
2).Singanayagam A. Hakki S. Dunning J. et al.
Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study.
Lancet Infect Dis. 2022; 22: 183-195
4) .Mao T. Israelow B. Peña-Hernández M.A. et al.Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses.
Science. 2022;
5) Fröberg J. Gillard J. Philipsen R. et al.
SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms. Nat Commun. 2021; 12: 5621
6)Cagigi A. Yu M. Österberg B. et al.
Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination.
JCI Insight [Internet]. 2021; 6 (Available from:) https://insight.jci.org/articles/view/151463
The question raised by Juan Ervriti and Colleagues (1) whether the obvious benefit of evolocumab is offset by a currently unknown risk is justified and of high clinical relevance. We know active ingredients that effectively lower the atherogenic lipopoproteins, but have an unfavorable benefit-risk ratio under the bottom line (2). Therefore, the raised concerns must be addressed.
The chosen methodology by Ervriti and Colleagues seems to me feasible, although not perfect. For a comprehensive reanalysis the raw data are required. Unfortunately they never received such data, although they have made many efforts to do so.
To my opinion, scientific misconduct – as intended by Sabatine et. al. (3) - is not the case with Evriti et al. but rather with the FOURIER authors and the study sponsor, who apparently never answered the questions that were put to them repeatedly and publicly (4).
The announcement by the FOURIER authors that they will respond to the accusations now promptly (3) is no longer sufficient. They are biased in a number of ways, but primarily because their scientific reputation is at stake. There is no other way to understand their rude reaction.
From my point of view, it is also highly irritating that neither EMA nor Health Canada seem to have scrutinized the case report forms (CRF) when they approved this new drug. It looks like they've never laid their hands on a FOURIER-CRF. If that is the case, then they trusted the investigators bl...
The question raised by Juan Ervriti and Colleagues (1) whether the obvious benefit of evolocumab is offset by a currently unknown risk is justified and of high clinical relevance. We know active ingredients that effectively lower the atherogenic lipopoproteins, but have an unfavorable benefit-risk ratio under the bottom line (2). Therefore, the raised concerns must be addressed.
The chosen methodology by Ervriti and Colleagues seems to me feasible, although not perfect. For a comprehensive reanalysis the raw data are required. Unfortunately they never received such data, although they have made many efforts to do so.
To my opinion, scientific misconduct – as intended by Sabatine et. al. (3) - is not the case with Evriti et al. but rather with the FOURIER authors and the study sponsor, who apparently never answered the questions that were put to them repeatedly and publicly (4).
The announcement by the FOURIER authors that they will respond to the accusations now promptly (3) is no longer sufficient. They are biased in a number of ways, but primarily because their scientific reputation is at stake. There is no other way to understand their rude reaction.
From my point of view, it is also highly irritating that neither EMA nor Health Canada seem to have scrutinized the case report forms (CRF) when they approved this new drug. It looks like they've never laid their hands on a FOURIER-CRF. If that is the case, then they trusted the investigators blindly and failed to do their job. This would disqualify theses institutions for a trusting reanalysis of the data.
Ultimately, only another independent reanalysis of the FOURIER raw data by a recognized independent institution should clarify the facts as soon as possible.
References:
1. Erviti J, Wright J, Bassett K, Ben-Eltriki M, Jauca C, Saiz LC, Leache L, Gutierrez-Valencia M and Perry TL. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data. BMJ open. 2022;12:e060172.
2. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321.
3. Marc S. Sabatine, MD, MPH, Stephen D. Wiviott, MD, Anthony C. Keech, MD, Peter S. Sever, PhD, FRCP and Robert P. Giugliano, MD, SM. Letter to the Editor RE: "Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data". BMJ Open. 2022;12:3060172.
Published on: 11 January 2023
4. Erviti J, et al. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data. BMJ Open 2022;12:e060172. doi: 10.1136/bmjopen-2021-060172
We thank Dr. Sabatine, Wiviott, Keech, Sever and Giuliano, who have posted Rapid Responses to our article (1), and are pleased that BMJ Open metrics indicate substantial interest.
We respectfully disagree with Dr. Sabatine et al., with regard to a number of issues they raise.
1. Dr. Sabatine and colleagues maintain that additional information available in patient dossiers and hospital records would have led us to different results. On the following dates: 13/02/2019, 18/03/2019, and 08/05/2019, we requested assistance to obtain such information from Dr. Sabatine, the corresponding author for the N Engl J Med 2017 report of FOURIER. Additionally, we emailed Dr Sabatine on 11/04/2019 to inform him that a ‘call-to-action’ on the FOURIER trial had been published in the BMJ (2) with the intention to restore the FOURIER trial. Neither Dr. Sabatine nor his colleagues made any reply.
The problems of event ascertainment, adjudication, and reporting in complex clinical trials will not go away without substantial changes. This is highlighted by the new Lancet inquiry into how the RECORD 4 trial of rivaroxaban was conducted and reported (3). The solution is openness and scientific collaboration, not “data hogging.”
Patients who volunteer for clinical trials enter an ethical agreement to help discover scientific truth. What would the same patients think if they realized that sponsors and investigators make sure that no one can effectively double check the...
We thank Dr. Sabatine, Wiviott, Keech, Sever and Giuliano, who have posted Rapid Responses to our article (1), and are pleased that BMJ Open metrics indicate substantial interest.
We respectfully disagree with Dr. Sabatine et al., with regard to a number of issues they raise.
1. Dr. Sabatine and colleagues maintain that additional information available in patient dossiers and hospital records would have led us to different results. On the following dates: 13/02/2019, 18/03/2019, and 08/05/2019, we requested assistance to obtain such information from Dr. Sabatine, the corresponding author for the N Engl J Med 2017 report of FOURIER. Additionally, we emailed Dr Sabatine on 11/04/2019 to inform him that a ‘call-to-action’ on the FOURIER trial had been published in the BMJ (2) with the intention to restore the FOURIER trial. Neither Dr. Sabatine nor his colleagues made any reply.
The problems of event ascertainment, adjudication, and reporting in complex clinical trials will not go away without substantial changes. This is highlighted by the new Lancet inquiry into how the RECORD 4 trial of rivaroxaban was conducted and reported (3). The solution is openness and scientific collaboration, not “data hogging.”
Patients who volunteer for clinical trials enter an ethical agreement to help discover scientific truth. What would the same patients think if they realized that sponsors and investigators make sure that no one can effectively double check their analyses? As Cochrane authors, we have obtained the individual-patient data of different trials to carry out systematic reviews that provide high added value to patients and health systems. There are no legal constraints nor ethical reasons to refuse to share anonymized data. We encourage Dr. Sabatine and colleagues to share the full database of the FOURIER trial with the scientific community.
2. Our re-adjudication of the deaths in FOURIER was done exclusively by a panel of 5 blinded re-adjudicators. Anything that could provide a hint as to treatment was redacted by a researcher from outside the panel before the narratives were seen by the re-adjudicators. We explained this in the publication and there should be no misunderstanding. Additionally, readers can double-check all re-adjudications made, their justification, and read the original narratives in the CSR that support all decisions taken (supplemental table S2).
3. We recruited as volunteer re-adjudicators JMW, KB, MBE, CJ and TLP, who have extensive experience in Clinical Pharmacology, Internal Medicine, Family Practice, Pharmacy, and critical appraisal. The 5 adjudicators took on this project during the Covid-19 pandemic as work additional to their University of British Columbia academic appointments. For the re-adjudications, we followed the definitions specified in the FOURIER trial protocol. For most sessions, all 5 were present to review each case, and never fewer than 4 re-adjudicators, operating by consensus. The role of TLP was to resolve any dispute, but in no case did this arise. The online supplement to our report provides all possible details when our re-adjudication diverged from the original adjudication by the FOURIER Clinical Events Committee.
4. In the FOURIER protocol there is no mention about autopsies being carried out. Had they been performed in the trial, this should have been included in the protocol. The Clinical Study Report (over 25 000 pages) provides no evidence of any autopsies. To the contrary, in a few cases, the narratives confirmed that an autopsy was not performed.
5. We applied a very conservative approach and re-adjudicated the cause of mortality only if there was compelling evidence in the CSR to support changes.
References:
1. Erviti J, Wright J, Bassett K, et alRestoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory dataBMJ Open 2022;12:e060172. doi: 10.1136/bmjopen-2021-060172
2. Erviti J, Saiz LC, Leache L. Rapid response to: Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ2013;346.
3. Demasi M. Rivaroxaban: Lancet opens investigation into anticlotting drug trial after BMJ report. BMJ. 2022 Dec 30;379:o3071. doi: 10.1136/bmj.o3071. PMID: 36585025.
It was interesting to read Buntine et al’s (1) experience with the Febridx Point of Care Device in the Accident and Emergency setting. They found a negative predictive value of 80% and a positive predictive value of 78%. The results from our study in general practice demonstrated a negative predictive value of 43%.
We commenced the use of the Febridx device in an Australian general practice in November 2020, just prior to the outbreak of Covid 19. Our study used clinical follow up, rather than biological markers to determine Febridx effectiveness.
Our study was designed to compare antibiotic prescribing in those doctors using the device to determine the difference between viral and bacterial illness compared to those doctors relying on their usual clinical skills. Our study was sabotaged by the advent of Covid 19 and the introduction of lockdowns, isolation, and telehealth. Like much of the country, we saw presentations for URTI’s and the subsequent use of all antibiotics, especially those associated with respiratory disease, decrease.
Our six-doctor general practice used Best Practice clinical software to determine the number of antibiotics prescribed and the number of patients seen each month for each doctor.
In the 6 months prior to covid epidemic, prescribing of respiratory antibiotics (Amoxycillin, Amoxycillin/Clavulanic acid, Cephalexin, Roxithromycin, Trimethoprim/sulfamethoxazole, Clindamycin, Ciproxin, penicillin) was 7.3 antibiotics...
It was interesting to read Buntine et al’s (1) experience with the Febridx Point of Care Device in the Accident and Emergency setting. They found a negative predictive value of 80% and a positive predictive value of 78%. The results from our study in general practice demonstrated a negative predictive value of 43%.
We commenced the use of the Febridx device in an Australian general practice in November 2020, just prior to the outbreak of Covid 19. Our study used clinical follow up, rather than biological markers to determine Febridx effectiveness.
Our study was designed to compare antibiotic prescribing in those doctors using the device to determine the difference between viral and bacterial illness compared to those doctors relying on their usual clinical skills. Our study was sabotaged by the advent of Covid 19 and the introduction of lockdowns, isolation, and telehealth. Like much of the country, we saw presentations for URTI’s and the subsequent use of all antibiotics, especially those associated with respiratory disease, decrease.
Our six-doctor general practice used Best Practice clinical software to determine the number of antibiotics prescribed and the number of patients seen each month for each doctor.
In the 6 months prior to covid epidemic, prescribing of respiratory antibiotics (Amoxycillin, Amoxycillin/Clavulanic acid, Cephalexin, Roxithromycin, Trimethoprim/sulfamethoxazole, Clindamycin, Ciproxin, penicillin) was 7.3 antibiotics prescriptions per 100 patient encounters. During the pandemic it fell to 4.4 prescriptions per 100 encounters. In the last 6 months it has risen to 7.2.
Prior to Covid taking over the community in February 2020 we were able to enrol 32 patients into our study and follow their progress. Thirty patients tested negative (one band). Two patients tested positive for bacterial infection with two bands and were treated with antibiotics. No patients tested positive for three bands ie viral infection. Subsequent follow up of all patients, a week later, resulted in 17(57%) of those in the negative Febridx test group requiring antibiotics for unresolved symptoms. Some of these patients had then been unwell for 6 weeks prior to their course of antibiotics.
This has led us to question the role of point of care testing in the general practice setting. Our practice has served our suburban community for 40 years. The patients have learnt to treat most URTI as viral and only present after prolonged symptoms. We suspect that this may have meant that first presentation was beyond the window of the Febridx’s usefulness which is now regarded as the first week of the illness and ideally associated with a fever (2). By introducing the Febridx late into the illness process we delayed the use of antibiotics and the patient’s recovery in over half (17/32) those in the study.
The study has been a useful audit of our practice antibiotic prescribing and highlighting the number of patients requiring antibiotics to get better. Whilst Febridx has demonstrated a usefulness in the accident and emergency setting it may be that time is still the most powerful diagnostic tool in general practice.
This study was supported by Lumos diagnostics who provided the Febridx devices for no cost. The Study was overseen by the University of Newcastle ethics committee.
References
1. Paul Buntine 1 2, Joseph Miller 3 2, Alun Pope 2 4, Stephen Guy 2 5, Fang Qi Alex Wong 6 7, Hannah McDonald 6 8, Mania Ahmed 2 9, Kang Hui Teow 2 10, Morgan Roney 1 2, Farzaneh Mohammadi 1 11, Emogene Aldridge 1 2, Liam Hackett 1 2, Susanna Jenner 1, Belinda Davis 1 Negative predictive value of the FebriDx host response point-of-care test in patients presenting to a single Australian emergency department with suspected COVID-19: an observational diagnostic accuracy study BMJ Open. 2022 Dec 29;12(12)
2. Shapiro NI, Self WH, Rosen J, Sharp SC, Filbin MR, Hou PC, et al. A prospective, multi-centre US clinical trial to determine accuracy of FebriDx point-of-care testing for acute upper respiratory infections with and without a confirmed fever. Ann Med. 2018;50(5):420-9.
Dear Sir
The article by Erviti et al. [1] is a provocative reinterpretation of the data from the FOURIER trial [2]. However, their conclusion indicating that clinicians should be ‘sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease’ is not adequately supported by the data provided.
First, global mortality did not statistically differ between placebo and evolocumab groups. Therefore, given that total mortality remains unchanged in both groups by Erviti’s analysis, any increase in cardiovascular mortality must be identical numerically to a reduction in non-cardiovascular (+ undetermined) mortality. The claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non cardiovascular mortality. Of note, the FORIER trial was not powered to discriminate the effect of evolocumab on cardiovascular and non cardiovascular mortality; this lack of power remains for Ertivi’s analysis: none of their concerns is supported by any statistically significant difference. Further speculation regarding other individual end point sub group analysis must be interpreted with caution: it is fun to look at, but do not believe them [3]. While it is worth carefully reviewing the adjudication of cardiovascular mortality, FOURIER open label extension study suggest that longer treatment with evolocumab may indeed reduce cardiovascular mortality. [4]
Even if we remain sceptical about a potential red...
Dear Sir
The article by Erviti et al. [1] is a provocative reinterpretation of the data from the FOURIER trial [2]. However, their conclusion indicating that clinicians should be ‘sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease’ is not adequately supported by the data provided.
First, global mortality did not statistically differ between placebo and evolocumab groups. Therefore, given that total mortality remains unchanged in both groups by Erviti’s analysis, any increase in cardiovascular mortality must be identical numerically to a reduction in non-cardiovascular (+ undetermined) mortality. The claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non cardiovascular mortality. Of note, the FORIER trial was not powered to discriminate the effect of evolocumab on cardiovascular and non cardiovascular mortality; this lack of power remains for Ertivi’s analysis: none of their concerns is supported by any statistically significant difference. Further speculation regarding other individual end point sub group analysis must be interpreted with caution: it is fun to look at, but do not believe them [3]. While it is worth carefully reviewing the adjudication of cardiovascular mortality, FOURIER open label extension study suggest that longer treatment with evolocumab may indeed reduce cardiovascular mortality. [4]
Even if we remain sceptical about a potential reduction in cardiovascular mortality by evolocumab, no one disputes its favourable effects not simply on lipid levels, but in cardiovascular event reduction in patients with established atherosclerotic cardiovascular disease., as it is the case for alirocumab The higher the extension of cardiovascular disease, the higher the potential absolute benefit of PCSK9 inhibition therapy [5].
With the present level of evidence our concern should not be that we are prescribing evolocumab for too many patients with cardiovascular disease. Rather, we should ask ourselves why so many atherosclerotic patients with uncontrolled LDL cholesterol levels are not receiving adequate lipid-lowering therapy, including PCSK.9 Inhibtors if required.
1 Erviti J, Wright J, Bassett K, et al. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data. BMJ Open 2022;12:e060172. doi:10.1136/bmjopen-2021-060172
2 Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine 2017;376:1713–22. doi:10.1056/NEJMoa1615664
3 Sleight P. Debate: Subgroup analyses in clinical trials: fun to look at - but don’t believe them! Curr Control Trials Cardiovasc Med 2000;1:25–7. doi:10.1186/cvm-1-1-025
4 O’Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease. Circulation 2022;146:1109–19. doi:10.1161/CIRCULATIONAHA.122.061620
5 Ascaso JF, Civeira F, Guijarro C, et al. Indications of PCSK9 inhibitors in clinical practice. Recommendations of the Spanish Sociey of Arteriosclerosis (SEA), 2019. Clin Investig Arterioscler 2019;31:128–39. doi:10.1016/j.arteri.2019.04.002
Most of the studies in the literature propagate that the incidence of frozen shoulder is higher in people with diabetes. According to the American Diabetic Association, the average age of people with frozen shoulder is 52 years. Among people 40 and over, the condition affects 2 to 4 percent of the general population and up to 25 percent of people with diabetes. But no definite pathophysiological mechanism to support the data has been postulated.
Several questions remain unanswered.
Do people with diabetes experience worse outcomes from frozen shoulders than those without diabetes?
Does uncontrolled diabetes have a higher risk or severity of disease?
Do people with diabetes develop frozen shoulder at an earlier age than non-diabetics?
Does Diabetes delay the recovery from a frozen shoulder?
Answers to the above questions may be yes in several studies in scientific literature. However, the certainty in evidence in most such studies is moderate to low. In our experience of more than 30 years, we also don't find any such correlation.
Frozen shoulder undoubtedly has a higher incidence among patients with Myocardial Infarction, but the incidence, duration of disability, severity of symptoms, and age of onset are not remarkably different from the general population.
References: 1.https://www.sciencedirect.com/science/article/pii/S259010952100051...
Show MoreThis research by Mooghali and team provide valuable and disturbing data on the problem of financial conflicts of interest (COI) in clinical practice guidelines.(1) Failure of authors and committee members to accurately disclose potential COI raises concerns about lack of transparency in the process, bias in the resulting guidelines, and ultimately harm to patients.
The pioneering work in this area was done by the American Academy of Family Physicians, which published in 1994 the first international call for an explicit declaration of conflicts of interest in the development of clinical practice guidelines.(2) This has been followed by policies on COI by other groups of primary care physicians in the US(3,4), the UK(5,6) and Canada(7,8).
Primary care physicians have been early champions of evidence-based medicine and explicit clinical practice guidelines. They are also the clinicians working at the point of care, partnering with patients to make shared decisions. The best in care requires the best guidance based on the best evidence. Therefore, potential COIs must be fully disclosed and critically managed by all involved in producing, disseminating, and implementing clinical practice guidelines.
Show MoreREFERENCES
1.Mooghali M, Glick L, Ramachandran R, et al. Financial conflicts of interest among US physician authors of 2020 clinical practice guidelines: a cross- sectional study. BMJ Open 2023;13:e069115. doi:10.1136/ bmjopen-2022-069115
2. Phillips...
hi-
This seems like a really interesting, and potentially very important study. I'm concerned though that you are not listing as a primary objective improving the CD4/CD8 ratio. While a home run could be decreasing the reservoir, whether you decrease the reservoir or not, you might improve the ratio and this by itself could alter future cancer susceptibility (anal, colon, lung) and may avoid zoster, or tb acquisition (if in India for example) and could improve immune response to vaccines. I'm not saying all of this naturally follows, but if you beat down CMV it is at least as likely that you make the immune system less distracted then it is you decrease the reservoir. Thanks for getting this together though and I look forward to the outcomes. Rob Striker UW Madison
While I agree with the conclusion of this research that it is necessary for the government to communicate uncertainties with the general public about public health and vaccination specifically in the COVID-19 era, I’m afraid that data of the present study was not able to support this conclusion.
Show MoreIn the emotions part of the result section, the authors reported that no significant between group differences of uncertainty was found in any circumstances, neither after receiving the announcement (p = .091), nor after reading the conflicting information (p = .462), or overall (p = .628). This result indicated that the intervention of the present study failed to manipulate different level of certainty between two intervention groups. All analysis and the corresponding results based on condition as independent variable tended to be invalid because it didn’t pass the manipulation check.
Under this circumstance, the level of uncertainty before intervention would be a more reasonable choice as the primary independent variable. The similar mediation model in the present study was tested with the level of uncertainty before intervention as independent variable and the vaccination intention after intervention as dependent variable. If trust in government representative and perceived vaccine effectiveness before intervention were tested as mediators in the model, indirect effects of both path were significant, with the trust path β = -0.0898, 95% CI = [-0.1401, -0.0426], and...
We thank Dr. Guijarro for his comments (1) and are pleased to respond to his main concerns on our article. He states that “the claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non-cardiovascular mortality”. However, we should bear in mind that both total and cardiovascular mortality were numerically increased in the evolocumab group compared to placebo, which is inconsistent with a significant reduction in cardiovascular events. Additionally, this drug is indicated for patients with previous cardiovascular disease. If potential cardiac harm were confirmed, additional concerns with evolocumab in this population would be reasonably expected.
We acknowledge that “none of our concerns is supported by any statistically significant difference”. However, since cardiovascular mortality is included in the composite primary endpoint, an exaggerated assessment of cardiovascular mortality could have contributed to inappropriate early termination of the trial ‘for benefit’. If the point estimate we identified of a 20% relative risk increase in cardiovascular mortality were maintained, the non-significant increase from evolocumab might have reached statistical significance before the end of the prespecified 56-month follow-up.
Dr. Guijarro also mentions that “the FOURIER open label extension study suggests that longer treatment with evolocumab may indeed reduce cardiovascular mortality”(2). However, the results of this study di...
Show MoreIntramuscular (i.m.) ChAdOx1 nCOV19 , trade name "covishield " vaccine of company astrazeneca and sub licensed with Serum Institute of India ( mRNA 1273 vaccine for Spike Protein /RBD) and of Bharat Biotech company's whole virion inactivated Vero cell "co vaccine" which were given to Indian population in two minimum doses( free of cost) , in India ,were remarkably effective in preventing severe COVID-19 pneumonia, ARDS and hospitalisation with all sub variants( VOC) of omicron variants of concern of SARS COV-2 ,those were circulated so far in India since 2021 March and their full dose ( two/ or precautionary 3rd doses in 27% Indians ) use being associated with declining hospitalisation , ARDS, ventilation and COVID 19 related death . However, current vaccines those are given by the Indian government's health department can provide only transient protection against respiratory SARS- COV -2 viral replications , onward transmission and continuing emergence of variants of concern, by contrast, respiratory infection with SARS-CoV-2 could induces more potent serum IGg and IGa antibody mediated ( against spike protein and RBD protein) immunity against breakthrough infections ( re- infection even after vaccination or after clinical or subclinical infection) , mucosal immune defences that could inhibit viral replication and transmission, but did not happened it so in real world . Although covishield/ or co vaccine i.m. vaccinations transi...
Show MoreThe question raised by Juan Ervriti and Colleagues (1) whether the obvious benefit of evolocumab is offset by a currently unknown risk is justified and of high clinical relevance. We know active ingredients that effectively lower the atherogenic lipopoproteins, but have an unfavorable benefit-risk ratio under the bottom line (2). Therefore, the raised concerns must be addressed.
Show MoreThe chosen methodology by Ervriti and Colleagues seems to me feasible, although not perfect. For a comprehensive reanalysis the raw data are required. Unfortunately they never received such data, although they have made many efforts to do so.
To my opinion, scientific misconduct – as intended by Sabatine et. al. (3) - is not the case with Evriti et al. but rather with the FOURIER authors and the study sponsor, who apparently never answered the questions that were put to them repeatedly and publicly (4).
The announcement by the FOURIER authors that they will respond to the accusations now promptly (3) is no longer sufficient. They are biased in a number of ways, but primarily because their scientific reputation is at stake. There is no other way to understand their rude reaction.
From my point of view, it is also highly irritating that neither EMA nor Health Canada seem to have scrutinized the case report forms (CRF) when they approved this new drug. It looks like they've never laid their hands on a FOURIER-CRF. If that is the case, then they trusted the investigators bl...
We thank Dr. Sabatine, Wiviott, Keech, Sever and Giuliano, who have posted Rapid Responses to our article (1), and are pleased that BMJ Open metrics indicate substantial interest.
We respectfully disagree with Dr. Sabatine et al., with regard to a number of issues they raise.
1. Dr. Sabatine and colleagues maintain that additional information available in patient dossiers and hospital records would have led us to different results. On the following dates: 13/02/2019, 18/03/2019, and 08/05/2019, we requested assistance to obtain such information from Dr. Sabatine, the corresponding author for the N Engl J Med 2017 report of FOURIER. Additionally, we emailed Dr Sabatine on 11/04/2019 to inform him that a ‘call-to-action’ on the FOURIER trial had been published in the BMJ (2) with the intention to restore the FOURIER trial. Neither Dr. Sabatine nor his colleagues made any reply.
The problems of event ascertainment, adjudication, and reporting in complex clinical trials will not go away without substantial changes. This is highlighted by the new Lancet inquiry into how the RECORD 4 trial of rivaroxaban was conducted and reported (3). The solution is openness and scientific collaboration, not “data hogging.”
Patients who volunteer for clinical trials enter an ethical agreement to help discover scientific truth. What would the same patients think if they realized that sponsors and investigators make sure that no one can effectively double check the...
Show MoreIt was interesting to read Buntine et al’s (1) experience with the Febridx Point of Care Device in the Accident and Emergency setting. They found a negative predictive value of 80% and a positive predictive value of 78%. The results from our study in general practice demonstrated a negative predictive value of 43%.
We commenced the use of the Febridx device in an Australian general practice in November 2020, just prior to the outbreak of Covid 19. Our study used clinical follow up, rather than biological markers to determine Febridx effectiveness.
Our study was designed to compare antibiotic prescribing in those doctors using the device to determine the difference between viral and bacterial illness compared to those doctors relying on their usual clinical skills. Our study was sabotaged by the advent of Covid 19 and the introduction of lockdowns, isolation, and telehealth. Like much of the country, we saw presentations for URTI’s and the subsequent use of all antibiotics, especially those associated with respiratory disease, decrease.
Our six-doctor general practice used Best Practice clinical software to determine the number of antibiotics prescribed and the number of patients seen each month for each doctor.
In the 6 months prior to covid epidemic, prescribing of respiratory antibiotics (Amoxycillin, Amoxycillin/Clavulanic acid, Cephalexin, Roxithromycin, Trimethoprim/sulfamethoxazole, Clindamycin, Ciproxin, penicillin) was 7.3 antibiotics...
Show MoreDear Sir
Show MoreThe article by Erviti et al. [1] is a provocative reinterpretation of the data from the FOURIER trial [2]. However, their conclusion indicating that clinicians should be ‘sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease’ is not adequately supported by the data provided.
First, global mortality did not statistically differ between placebo and evolocumab groups. Therefore, given that total mortality remains unchanged in both groups by Erviti’s analysis, any increase in cardiovascular mortality must be identical numerically to a reduction in non-cardiovascular (+ undetermined) mortality. The claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non cardiovascular mortality. Of note, the FORIER trial was not powered to discriminate the effect of evolocumab on cardiovascular and non cardiovascular mortality; this lack of power remains for Ertivi’s analysis: none of their concerns is supported by any statistically significant difference. Further speculation regarding other individual end point sub group analysis must be interpreted with caution: it is fun to look at, but do not believe them [3]. While it is worth carefully reviewing the adjudication of cardiovascular mortality, FOURIER open label extension study suggest that longer treatment with evolocumab may indeed reduce cardiovascular mortality. [4]
Even if we remain sceptical about a potential red...
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