Comorbidities: Hypertension and cardiovascular comorbidities

Hypertension and cardiovascular co-morbidities

From the beginning of the pandemic, hypertension and/or cardiovascular disease (CVD) have been identified as potential risk factors for severe disease and death (Table 1). However, all studies were retrospective, included only hospitalized patients and did not distinguish between uncontrolled and controlled hypertension or used different definitions for CVD. Multivariate analyses adjusting for confounders were performed in only a few studies. Moreover, different outcomes and patient groups were analyzed. According to some experts, current data do not necessarily imply a causal relationship between hypertension and severity of COVID-19. There is no study that demonstrates the independent predictive value of hypertension. It is “unclear whether uncontrolled blood pressure is a risk factor for acquiring COVID-19, or whether controlled blood pressure among patients with hypertension is or is not less of a risk factor” (Schiffrin 2020). The same applies to CVD, with the difference that the numbers here are even lower.

From a mechanistic point of view, however, it seems plausible that patients with underlying cardiovascular diseases and pre-existing damage to blood vessels such as artherosclerosis may face higher risks for severe diseases. During recent weeks, it has become clear that SARS-CoV-2 may directly or indirectly attack the heart, kidney and blood vessels. Various cardiac manifestations of COVID-19 do occur contemporarily in many patients (see chapter Clinical Presentation, page 293). Infection may lead to cardiac muscle damage, blood vessel constriction and to elevated levels of inflammation-inducing cytokines. These direct and indirect adverse effects of the virus may be especially deleterious in those with already established heart disease. During the next months, we will learn more about the role and contributions of arteriosclerosis in the pathogenesis of COVID-19.

 

Table 1. Hypertension in larger cohort studies, prevalence and outcome
Study Setting Hypertension present? Multivariate, hazard or odds ratio (95% CI) for endpoint
Wang 2020 344 ICU pts,
Tongji, China
Survivors vs Non-Survivors: 34 vs 52% Not done
Grasselli 2020 521 ICU pts,
72 hospitals in Italy
Discharge from ICU vs death at ICU: 40 vs 63% Not done
Guan 2020 1099 hospitalized pts, 522 hospitals in China Non-severe disease vs severe: 13 vs 24% Not done
Zhou 2020 191 hospitalized pts from Jinyintan and Wuhan Survivors vs Non-Survivors: 23 vs 48% Not done
Shi 2020 487 hospitalized pts
in Zhejing Province
Non-severe disease at admission vs severe:
17 vs 53%
OR 2,7 (1,3-5,6) for severe disease at admission
Guan 2020 1590 hospitalized pts, 575 hospitals in China Non-severe vs severe courses: 13 vs 33% HR 1,6 (1,1-2,3) for severe course (ICU, IMV, death)
Goyal 2020 393 hospitalized pts,
2 hospitals in New York
No IMV vs IMV during stay: 48 vs 54% Not done

IMV invasive mechanical ventilation, ICU intensive care units

Treatment of hypertension during the pandemic

There has hardly been a topic that has kept doctors and their patients as busy as the question of whether antihypertensive drugs such as ACE inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) can cause harm to patients. The uncontrolled observations of increased mortality risk in patients with hypertension, CVD (see above) and diabetes raised concerns. These conditions share underlying renin-angiotensin-aldosterone system pathophysiology that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated (increased) in cardiovascular disease (Vaduganathan 2020). As SARS-CoV-2 cell entry depends on ACE2 (Hoffmann 2020), increased ACE2 levels may increase the virulence of the virus within the lung and heart.

There is a large study that examined the association between pre-infection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England (Sheppard 2020). Eligible patients were adults with hypertension who were diagnosed with COVID-19. A total of 4277 patients (9,4%) were diagnosed with COVID-19 and 877 died within 28 days. There was no association between BP control and COVID-19 diagnosis or hospitalization. Of note, individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (OR 0,76, 95%CI: 0,62-0,92) compared to patients with well-controlled BP. However, these patients were older, had more co-morbidities and had been diagnosed with hypertension for longer, suggesting more advanced atherosclerosis and target organ damage.

ACEIs or ARBs may alter ACE2, and variation in ACE2 expression may in part be responsible for disease virulence. However, the first substantial study to examine the association between plasma ACE2 concentrations and the use of ACEIs/ARBs did not support this hypothesis: in two large cohorts from the pre-COVID-19 era, plasma concentrations of ACE2 were markedly higher in men than in women, but not with ACEI/ARB use (Sama 2020). A recent review of 12 animal studies and 12 human studies overwhelmingly implies that administration of both drug classes does not increase ACE2 expression (Sriram 2020).

However, some concerns on deleterious effects continue and some media sources and even scientific papers have called for the discontinuation of these drugs. This is remarkable as almost no clinical study showed any evidence of harm.

  • Among 2573 COVID-19 patients with hypertension from New York City, there were no differences in the likelihood for severe COVID-19 for different classes of antihypertensive medications – ACE inhibitors, ARBs, beta blockers, calcium channel blockers, and thiazide diuretics (Reynolds 2020).
  • Comparing 6272 Italian cases (positive for SARS-CoV-2) to 30,759 controls (matched for sex, age, and municipality of residence), no evidence was found that ACE inhibitors or ARBs modify susceptibility to COVID-19 (Mancia 2020). The results applied to both sexes as well as to younger and older persons.
  • In a retrospective study from Denmark (one of the countries with the best epidemiological data) of 4480 COVID-19 patients, prior ACEI/ARB use, compared with no use, was not significantly associated with mortality. In a nested case-control study of a cohort of 494.170 patients with hypertension, use of ACEI/ARB, compared with use of other antihypertensive medications, was not significantly associated with COVID-19 diagnosis (Fosbøl 2020).
  • In a multicenter cohort study following more than 1,3 million patients with hypertension from the USA and Spain, no clear association of increased risk of COVID-19 diagnosis, hospital admission, or subsequent complications was seen with the outpatient use of ACEI or ARB. Furthermore, the marginal difference between ACEIs and ARBs does not warrant class switching (Morales 2020).
  • Does discontinuation compared with continuation of ACEIs or ARBs change anything? No. In an open label RCT that included 659 patients from Brazil who were hospitalized with mild to moderate COVID-19 who were taking ACEIs or ARBs before hospital admission, the mean number of days alive and out of the hospital for those assigned to discontinue versus continue these medications was 21,9 vs 22,9, respectively (Lopes 2020).

In conclusion, ACE inhibitors and/or ARBs should not be discontinued. Several other RCT plan to evaluate ACEIs and ARBs for treatment of COVID-19 (Mackey 2020). According to a brief review, adjuvant treatment and continuation of pre-existing statin therapy could improve the clinical course of patients with COVID-19, either by their immunomodulatory action or by preventing cardiovascular damage (Castiglion 2020). In a retrospective study on 13.981 patients in Hubei Province, China, the use of statins was independently associated with lower all-cause mortality (5,2% vs 9,4%). However, an observational cohort study using data from Danish nationwide registries, 843/4842 (17%) COVID-19 patients redeemed a prescription of statins in the 6 months prior to COVID-19 diagnosis. Recent statin exposure was not associated with an increased or decreased risk of all-cause mortality or severe infection (Butt 2020). Randomized controlled trials involving statin treatment for COVID-19 are needed.

Treatment of coronary heart disease during the pandemic

Pre-existing cardiovascular disease is linked with higher morbidity and mortality in patients with COVID-19, whereas COVID-19 itself can induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism (nice review: Nishiga 2020). Myocardial injury, evidenced by elevated cardiac biomarkers, was recognized among early cases and myocardial infarction (STEMI or NSTEMI) and may represent the first clinical manifestation of COVID-19. Of note, a culprit lesion is often not identifiable by coronary angiography. In a study of 28 patients with STEMI, this was the case in 39% (Stefanini 2020). According to the authors, a dedicated diagnostic pathway should be delineated for COVID-19 patients with STEMI, aimed at minimizing procedural risks and healthcare providers’ risk of infection. There are already preliminary reports on a significant decline of 32% in the number of percutaneous coronary interventions for acute coronary syndromes (Piccolo 2020). Other authors have suggested that, in settings with limited resources to protect the work force, fibrinolytic therapies may be preferred over primary percutaneous coronary interventions (Daniels 2020).

In a meta-analysis, outcomes of 50.123 patients from 10 studies were assessed. Data showed that acute and timely medical care of these patients had been maintained during the pandemic in most countries. Consequently, despite a significant reduction in overall admission rates of patients with STEMI during the COVID-19 pandemic, there was no significant difference in hospital mortality compared with patients with STEMI admitted before the outbreak (Rattka).

Of note, several studies have found a spectacular drop in admissions for STEMI during the peak of the epidemic. In France a steep decline of 25% was found for both acute ( < 24hrs) and late presentation (> 24 hrs) STEMI (Rangé 2020). Similar observations have been made in Italy (De Filippo 2020) and the US (Solomon 2020). Possible explanations for this phenomenon may be patients’ fear of coming to the hospital or disturbing busy caregivers, especially in the case of mild STEMI clinical presentation. Other hypothetical reasons are reduced air pollution, better adherence to treatment, limited physical activity or absence of occupational stress during lockdown. However, there is some evidence that the lower incidence does not reflect a true decline but just one more collateral damage of the pandemic. For example, Italian researchers have found a 58% increase of out-of-hospital cardiac arrests in March 2020 compared to the same period in 2019 (Baldi 2020). In New York, this increase seemed to be even more pronounced (Lai 2020). Others have observed an increased observed/expected mortality ratio during the early COVID-19 period indicating that patients try to avoid hospitalization (Gluckman 2020).

References

Baldi E, Sechi GM, Mare C, et al. Out-of-Hospital Cardiac Arrest during the Covid-19 Outbreak in Italy. N Engl J Med. 2020 Apr 29. PubMed: https://pubmed.gov/32348640. Full-text: https://doi.org/10.1056/NEJMc2010418

Bernhardt D, Wick W, Weiss SE, et al. Neuro-oncology Management During the COVID-19 Pandemic With a Focus on WHO Grade III and IV Gliomas. Neuro Oncol. 2020 May 5;22(7):928-35. PubMed: https://pubmed.gov/32369601. Full-text: https://doi.org/10.1093/neuonc/noaa113

Butt JH, Gerds TA, Schou M, et al. Association between statin use and outcomes in patients with coronavirus disease 2019 (COVID-19): a na-tionwide cohort study. BMJ Open. 2020 Dec 4;10(12):e044421. Pub-Med: https://pubmed.gov/33277291. Full-text: https://doi.org/10.1136/bmjopen-2020-044421

Castiglione V, Chiriacò M, Emdin M, Taddei S, Vergaro G. Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):258-259. PubMed: https://pubmed.gov/32347925. Full-text: https://doi.org/10.1093/ehjcvp/pvaa042

Daniels MJ, Cohen MG, Bavry AA, Kumbhani DJ. Reperfusion of STEMI in the COVID-19 Era – Business as Usual? Circulation. 2020 Apr 13. PubMed: https://pubmed.gov/32282225. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047122

De Filippo O, D’Ascenzo F, Angelini F, et al. Reduced Rate of Hospital Admissions for ACS during Covid-19 Outbreak in Northern Italy. N Engl J Med. 2020 Jul 2;383(1):88-89. PubMed: https://pubmed.gov/32343497. Full-text: https://doi.org/10.1056/NEJMc2009166

Fosbøl EL, Butt JH, Østergaard L, et al. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality. JAMA. 2020 Jul 14;324(2):168-177. PubMed: https://pubmed.gov/32558877. Full-text: https://doi.org/10.1001/jama.2020.11301

Frieden IJ, Puttgen KB, Drolet BA, et al. Management of Infantile Hemangiomas during the COVID Pandemic. Pediatr Dermatol. 2020 Apr 16. PubMed: https://pubmed.gov/32298480. Full-text: https://doi.org/10.1111/pde.14196

Gluckman TJ, Wilson MA, Chiu ST, et al. Case Rates, Treatment Approaches, and Outcomes in Acute Myocardial Infarction During the Coronavirus Disease 2019 Pandemic. JAMA Cardiol. 2020 Aug 7:e203629. PubMed: https://pubmed.gov/32766756. Full-text: https://doi.org/10.1001/jamacardio.2020.3629

Goyal P, Choi JJ, Pinheiro LC, et al. Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020 Apr 17. PubMed: https://pubmed.gov/32302078. Full-text: https://doi.org/10.1056/NEJMc2010419

Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. pii: 2764365. PubMed: https://pubmed.gov/32250385. Full-text: https://doi.org/10.1001/jama.2020.5394

Guan WJ, Liang WH, Zhao Y, et al. Co-morbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. Eur Respir J. 2020 Mar 26. PubMed: https://pubmed.gov/32217650. Full-text: https://doi.org/10.1183/13993003.00547-2020

Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. PubMed: https://pubmed.gov/32109013. Full-text: https://doi.org/10.1056/NEJMoa2002032

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. Cell. 2020 Mar 4. PubMed: https://pubmed.gov/32142651. Full-text: https://doi.org/10.1016/j.cell.2020.02.052

Lai PH, Lancet EA, Weiden MD, et al. Characteristics Associated With Out-of-Hospital Cardiac Arrests and Resuscitations During the Novel Coronavirus Disease 2019 Pandemic in New York City. JAMA Cardiol. 2020 Jun 19;5(10):1154-63. PubMed: https://pubmed.gov/32558876. Full-text: https://doi.org/10.1001/jamacardio.2020.2488

Leonardi A, Fauquert JL, Doan S, et al. Managing ocular allergy in the time of COVID-19. Allergy. 2020 Sep;75(9):2399-2402. PubMed: https://pubmed.gov/32402114. Full-text: https://doi.org/10.1111/all.14361

Lopes RD, Macedo AV, Silva P, et al. Effect of Discontinuing vs Continu-ing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Re-ceptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. JAMA January 19, 2021; 325(3):254-264. doi: 10.1001/jama.2020.25864

Mackey K, Kansagara D, Vela K. Update Alert 2: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 Jul 23. PubMed: https://pubmed.gov/32701362. Full-text: https://doi.org/10.7326/L20-0969

Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020 Jun 18;382(25):2431-2440. PubMed: https://pubmed.gov/32356627. Full-text: https://doi.org/10.1056/NEJMoa2006923

Mattei A, Amy de la Bretèque B, Crestani S, et al. Guidelines of clinical practice for the management of swallowing disorders and recent dysphonia in the context of the COVID-19 pandemic. Eur Ann Otorhinolaryngol Head Neck Dis. 2020 May;137(3):173-175. PubMed: https://pubmed.gov/32332004. Full-text: https://doi.org/10.1016/j.anorl.2020.04.011

Meng Y, Wu P, Lu W, et al. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: A retrospective study of 168 severe patients. PLoS Pathog. 2020 Apr 28;16(4):e1008520. PubMed: https://pubmed.gov/32343745. Full-text: https://doi.org/10.1371/journal.ppat.1008520. eCollection 2020 Apr

Mistrangelo M, Naldini G, Morino M. Do we really need guidelines for HRA during COVID-19 pandemic? Colorectal Dis. 2020 May 7. PubMed: https://pubmed.gov/32379928. Full-text: https://doi.org/10.1111/codi.15116

Morales DR, Conover MM, You SC, et al. Renin–angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analy-sis. Lancet Digital Health December 17, 2020. Full-text: https://doi.org/10.1016/S2589-7500(20)30289-2

Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol. 2020 Sep;17(9):543-558. PubMed: https://pubmed.gov/32690910. Full-text: https://doi.org/10.1038/s41569-020-0413-9

Piccolo R, Bruzzese D, Mauro C, et al. Population Trends in Rates of Percutaneous Coronary Revascularization for Acute Coronary Syndromes Associated with the COVID-19 Outbreak. Circulation. 2020 Apr 30. PubMed: https://pubmed.gov/32352318. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047457

Rangé G, Hakim R, Motreff P. Where have the ST-segment elevation myocardial infarctions gone during COVID-19 lockdown? Eur Heart J Qual Care Clin Outcomes. 2020 Jul 1;6(3):223-224. PubMed: https://pubmed.gov/32348457. Full-text: https://doi.org/10.1093/ehjqcco/qcaa034

Rattka M, Dreyhaupt J, Winsauer C, et al. Effect of the COVID-19 pandemic on mortality of patients with STEMI: a systematic review and meta-analysis. Heart. 2020 Dec 17:heartjnl-2020-318360. PubMed: https://pubmed.gov/33334863. Full-text: https://doi.org/10.1136/heartjnl-2020-318360

Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020 May 1. PubMed: https://pubmed.gov/32356628. Full-text: https://doi.org/10.1056/NEJMoa2008975

Salgarello M, Adesi LB, Visconti G, Pagliara DM, Mangialardi ML. Considerations for performing immediate breast reconstruction during the COVID-19 pandemic. Breast J. 2020 May 7. PubMed: https://pubmed.gov/32383321. Full-text: https://doi.org/10.1111/tbj.13876

Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020 May 14;41(19):1810-1817. PubMed: https://pubmed.gov/32388565. Full-text: https://doi.org/10.1093/eurheartj/ehaa373

Schiffrin EL, Flack J, Ito S, Muntner P, Webb C. Hypertension and COVID-19. Am J Hypertens. 2020 Apr 6. pii: 5816609. PubMed: https://pubmed.gov/32251498. Full-text: https://doi.org/10.1093/ajh/hpaa057

Sheppard JP, Nicholson B, Lee J, et al. The association between blood pres-sure control and Coronavirus Disease 2019 outcomes in 45,418 symptomatic patients with hypertension: An observational cohort study. Hypertension. 2020 Dec 16. PubMed: https://pubmed.gov/33325240. Full-text: https://doi.org/10.1161/HYPERTENSIONAHA.120.16472

Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Crit Care. 2020 Mar 18;24(1):108. PubMed: https://pubmed.gov/32188484. Full-text: https://doi.org/10.1186/s13054-020-2833-7

Solomon MD, McNulty EJ, Rana JS, et al. The Covid-19 Pandemic and the Incidence of Acute Myocardial Infarction. N Engl J Med. 2020 Aug 13;383(7):691-693. PubMed: https://pubmed.gov/32427432. Full-text: https://doi.org/10.1056/NEJMc2015630

Stefanini GG, Montorfano M, Trabattoni D, et al. ST-Elevation Myocardial Infarction in Patients with COVID-19: Clinical and Angiographic Outcomes. Circulation. 2020 Apr 30. PubMed: https://pubmed.gov/32352306. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047525

Szperka CL, Ailani J, Barmherzig R, et al. Migraine Care in the Era of COVID-19: Clinical Pearls and Plea to Insurers. Headache. 2020 May;60(5):833-842. PubMed: https://pubmed.gov/32227596. Full-text: https://doi.org/10.1111/head.13810

Wang Y, Lu X, Chen H, et al. Clinical Course and Outcomes of 344 Intensive Care Patients with COVID-19. Am J Respir Crit Care Med. 2020 Apr 8. PubMed: https://pubmed.gov/32267160. Full-text: https://doi.org/10.1164/rccm.202003-0736LE

Zhang XJ, Qin JJ, Cheng X, et al. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020 Aug 4;32(2):176-187.e4. PubMed: https://pubmed.gov/32592657. Full-text: https://doi.org/10.1016/j.cmet.2020.06.015

Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 11. PubMed: https://pubmed.gov/32171076. Full-text: https://doi.org/10.1016/S0140-6736(20)30566-3