There is a suggestion that the use of a specific drug class, angiotensin converting enzyme (ACE) inhibitors, may reduce the risk of rupture of the larger aneurysms. This trial will assess whether an ACE inhibitor (perindopril) has aneurysm-related benefits, in patients with small AAAs at screening centres in the London area. Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. 1 2 They work by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.
ACE inhibitors up regulate (increase) the ACE2 receptor. This is the receptor the COVID-19 virus uses to attack the lungs.
Why is hypertension appearing to be a primary driver of COVID-19?
The incidence of hypertension is noticeably high in patients with COVID-19 and the high degree of targeting of older individuals is very unusual. A recent study by the US Centers for Disease Control and Prevention regarding the Kirkland Nursing home observed: “The most common chronic underlying conditions among facility residents were hypertension (69.1%), cardiac disease (56.8%), renal disease (43.2%), diabetes (37.0%), obesity (33.3%), and pulmonary disease (32.1%).”1
Thus, hypertension may be a primary risk factor and driver of the severe symptoms of COVID-19. Omnioutliner pro 5 5 3 3. The ACE2 Receptor is used by the coronavirus (SARS-CoV-2) to enter cells. A protease, TMPRSS2, is also required to prime the virus for cellular entry. Data suggests that serum of patients which have recovered from infection blocks this entry mechanism.2
In a recent blog, the director of the National Institutes of Health, Francis S. Collins, stated:“The genomic data of the new coronavirus responsible for COVID-19 show that its spike protein contains some unique adaptations. One of these adaptations provides special ability of this coronavirus to bind to a specific protein on human cells called angiotensin converting enzyme (ACE2).”3
Other researchers have observed that lisinopril and losartan can increase (or upregulate) the ACE2 Receptor mRNA cellular expression by five and three-fold, respectively.4 This has given rise to concerns that these inhibitors may increase ACE2 Receptor cellular surface expression leading to exacerbated viral load in cells.
There has been at least 1 review article which discusses this concern which recommended staying the course with ACE inhibitor therapy of hypertension, since it has also been observed to be protective of pulmonary damage in mice.5 The authors also appear to have a large number of declared conflicts-of-Interest with the drug industry. The laboratory research in mice used losartan (angiotensin II receptor antagonist) with an acute exposure not specified, and may not be adequate time for upregulation of ACE-2 receptor.6 In a prior publication, only a 30 minute pre-treatment of the inhibitor was used and the effect on ACE-2 receptor expression is unknown and therefore long-term viral effect on the lung cannot be determined.7
There is mounting consensus that ACE inhibitors may be a primary driver of the severe symptoms. The concerns have been raised in the Lancet8 and most recently in Medscape.9
If this is all true, then we may have identified how to mitigate the major pathology in COVID-19 and (similar to Tamiflu) have a mechanism of researching an exciting new therapy for this disease. Already, there is current research on Recombinant Human Angiotensin-converting Enzyme 2 at Clinicaltrials.gov #NCT04287686 and a blocker of TMPRSS2, camostat mesylate, has been approved for human use in Japan for another indication.2
(Acknowledgement: Lindsay E. Calderon, PhD, MPH, Eastern Kentucky University, was a co-author on this update and responsible for research analysis.)
(1) https://assets.documentcloud.org/documents/6812675/CDC-Life-Care-Center-of-Kirkland.pdf
(2) Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cel. Mar. 4, 2020 [Online ahead of print] https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)30229-4
(3) Collins, F. Genomic Study Points to Natural Origin of COVID-19. NIH Director’s Blog. Mar. 26, 2020. https://directorsblog.nih.gov/2020/03/26/genomic-research-points-to-natural-origin-of-covid-19/
(4) Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ. Feb. 28, 2020. Vol. 368. https://www.bmj.com/content/368/bmj.m810/rr-2
(5) Kuster GM, Pfister O, Burkard, T, et al. SARS-CoV2: should inhibitors of the renin–angiotensin systembe withdrawn in patients with COVID-19? European Heart Journal. 2020. 0:1–3. https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479
(6) Kuba K., Imai Y, Rao S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nature Medicine. Aug. 2005. 11(8):875-879. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095783/pdf/41591_2005_Article_BFnm1267.pdf
(7) Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. July 7, 2005. 436:112-116. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094998/
(8) Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory Medicine. March 11, 2020. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
(9) Hughes S. COVID-19 and Angiotensin Drugs: Help or Harm?. Medscape. March 25, 2020. https://www.medscape.com/viewarticle/927542
Stopping an ACE inhibitor or angiotensin receptor blocker (ARB) at admission for COVID-19 doesn't help outcomes, even for high-risk groups, the BRACE CORONA randomized trial showed.
Continuing these drugs for patients on them before admission if anything yielded numerically more days alive and out of the hospital at 30 days compared with temporarily suspending use (mean 22.9 vs 21.9, P=0.09).
Proportion of patients alive and out of the hospital at day 30 came out similar as well (95.0% continuing vs 91.8%), reported Renato Lopes, MD, PhD, of Duke Clinical Research Institute in Durham, North Carolina, at the European Cardiology Society (ESC) virtual meeting.
All-cause mortality at 30 days was 2.8% with continued use vs 2.7% with temporary stopping the drugs (HR 0.97, 95% CI 0.38-2.52).
'Our results endorse now with more reliable and definitive data what the societies have recommended,' which was an expert consensus based on observational data that patients should not stop ACE/ARB drugs over COVID-19 concerns, Lopes told MedPage Today at a press briefing for the ESC hot-line session.
Observational data had supported that recommendation, but there was theoretical risk that ACE inhibitors and ARBs could increase expression of the ACE2 receptors that the SARS-CoV-2 virus binds to and enhances its entry into cells, leading to worse outcomes.
Hadley Wilson, MD, of Sanger Heart & Vascular Institute in Charlotte, North Carolina, called the results 'very reassuring' for safety.
'We certainly don't want to have to discontinue these drugs unless they're harmful,' and if anything there was a weak trend for benefit that could have become significant with longer follow-up or larger numbers, he said. 'This is a large enough randomized trial that I can say with some certainty that this issue is settled.'
However, ESC session study discussant Gianfranco Parati, MD, of the University of Milano-Bicocca in Italy, said the 'results are probably not the last word, and it could be difficult to translate them in daily practice without considering the combined contribution of age and comorbidities to mortality risk in COVID-19 patients.'
The trial included 695 adults hospitalized in Brazil with confirmed COVID-19 who were chronic (median 5 years) users of ACE inhibitors (17%) or ARBs (83%). They were randomized to temporarily suspend those drugs for 30 days or continue use.
All the patients had hypertension; only 1% had heart failure. About 40% were women, mean age was 56, and 52% were obese. COVID-19 severity in the first 24 hours after presentation was mild for 57% and moderate for 43%. Severe cases were excluded because 'those patients are usually in shock,' Lopes said. 'Obviously, all the antihypertensive drugs need to be dropped.'
Patients were excluded if they had a hospitalization due to decompensated heart failure in the prior 12 months, use of more than three antihypertensives, use of sacubitril/valsartan (Entresto), or hemodynamic instability in the first 24 hours until confirmation of COVID-19 diagnosis.
Secondary outcomes showing no difference between treatment groups included:
Subgroup analyses likewise showed no difference by age, obesity, oxygen saturation at presentation, duration from symptom onset to randomization, degree of lung involvement, and COVID-19 severity at presentation.
Notably, about a quarter of the patients were age 65 and older. Parati said his group's experience has been that there is a difference in outcomes for older but not younger patients. However, Lopes noted that formal interaction analysis didn't turn up a significant difference by age, although numerically there was a greater benefit to continuing these drugs in the older group. The same was true for sicker patients and those with more comorbidities, he said.
'The message is pretty clear,' Wilson concluded. He noted that this is one of the first randomized trials to be completed in the cardiovascular field dealing with SARS-CoV-2.
Video changer software. 'The investigators should be congratulated on the speed with which they were able to enroll a large number of patients and get results,' he told MedPage Today. 'Their timeline was quite impressive, starting some of the first patients as early as April.'
Whereas some trialists have reported struggling to clear the bureaucratic hurdles to enrolling patients for antithrombotic trials, for example, in COVID-19 hospitalized patients, Wilson noted that the design of this trial in stopping rather than starting a treatment gave the researchers a logistical headstart.
Parati noted that patients were not stratified by ACE inhibitor versus ARB use in randomization -- a limitation since those drugs have different mechanisms of action. Also, he acknowledged the difficulty in assessing mortality risk over such a short follow-up period in a moderate-risk, relatively young cohort. As well, data were lacking on the drugs used for COVID-19 treatment in the cohort.
In addition, Parati argued, short-term suspension of ACE inhibitors and ARBs can't be considered equivalent to never taking them, since they have long-lasting effects that persist due to structural and not only functional changes with chronic use.
https://downhload511.weebly.com/arturia-spark-2-v2-0-1-download-free.html. Disclosures
BRACE CORONA trial was supported by D'Or Institute for Research and Education and the Brazilian Clinical Research Institute.
Lopes disclosed relevant relationships with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Portola.
Wilson and Parati disclosed no relevant relationships with industry.
http://krszhl.xtgem.com/Blog/__xtblog_entry/18987036-meldaproduction-maudioplugins-11-09#xt_blog. Primary Source Tipard dvd ripper for mac 9 2 2016.
European Society of Cardiology
Source Reference: Lopes R, et al 'BRACE CORONA: Continuing vs. Suspending ACE Inhibitors and ARBs in COVID-19' ESC 2020.
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