DiNicolantonio and McCarty suggest that the inverse association between low cholesterol and mortality in elderly people reflects reverse causality; meaning that the low cholesterol is caused by the disorder being treated.1 One of their arguments is that those whose cholesterol decreases with increasing age die more frequently from cancer and other diseases, compared to those with low cholesterol prior to treatment. However, many studies have shown that low cholesterol may predispose to cancer2 as well as infectious diseases.3 In a previous paper2 we identified nine cohort studies including more than 140,000 individuals, in which cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years.
The authors claim that statin treatment does not increase the risk of cancer based on a meta-analysis of 27 randomised trials published by the Cholesterol Treatment Trialists’ (CTT) Collaborators. But very few statin trials have continued for more than five years, and most carcinogenic chemicals need more time to create cancer. In spite of that cancer appeared significantly more often in three statin trials (2). In two other trials, non-melanoma skin cancer appeared more often and with statistical significance if the figures from the two trials were calculated together (2). Since then the number of non-melanoma skin cancers has not been reported in any trial. Fu...
DiNicolantonio and McCarty suggest that the inverse association between low cholesterol and mortality in elderly people reflects reverse causality; meaning that the low cholesterol is caused by the disorder being treated.1 One of their arguments is that those whose cholesterol decreases with increasing age die more frequently from cancer and other diseases, compared to those with low cholesterol prior to treatment. However, many studies have shown that low cholesterol may predispose to cancer2 as well as infectious diseases.3 In a previous paper2 we identified nine cohort studies including more than 140,000 individuals, in which cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years.
The authors claim that statin treatment does not increase the risk of cancer based on a meta-analysis of 27 randomised trials published by the Cholesterol Treatment Trialists’ (CTT) Collaborators. But very few statin trials have continued for more than five years, and most carcinogenic chemicals need more time to create cancer. In spite of that cancer appeared significantly more often in three statin trials (2). In two other trials, non-melanoma skin cancer appeared more often and with statistical significance if the figures from the two trials were calculated together (2). Since then the number of non-melanoma skin cancers has not been reported in any trial. Furthermore, cancer has been associated with statin treatment in several cohort and case–control studies as well (2), and also in several animal experiments (2).
There is a massive documentation to support the claim that low LDL-C predisposes to infectious diseases (3). In a meta-analysis of 19 cohort studies that included 68,406 deaths, Jacobs et al. found an inverse association between cholesterol and mortality from respiratory and gastrointestinal diseases, most of which are due to infections (3). It is unlikely that these diseases caused low cholesterol because these associations persisted after the exclusion of deaths occurring during the first 5 years.
Additional support comes from a 15-year follow-up study of more than 120,000 individuals by Iribarren et al. They found a strong inverse association between cholesterol as determined initially, and the subsequent risk of being admitted to hospital due to an infectious disease (3). Obviously, a disease they had not yet achieved could not have caused their low cholesterol.
DiNicolantonio and McCarty believe that the most conclusive evidence disputing a causal relationship between low LDL-C and cancer is provided by Mendelian randomisation, according to which none of the genotypes linked to lower LDL-C are associated with higher cancer risk. But association does not mean causation. Other genes in the same individual may have opposite effects, and as pointed out by Burgess et al: ”Power, linkage disequilibrium, pleiotropy, canalization and population stratification have all been recognized as potential flaws in the Mendelian randomization approach”.5
They also suggest that a high plasma level of interleukin-6 (IL-6) lowers LDL-C and that high IL-6 is the real cause of increased mortality because it is associated with higher rates global mortality in the elderly. However, it is also associated with various infections as well,6,7 which could be another explanation. What is little known, although it has been documented again and again by at least a dozen research groups, is that LDL partakes in the immune system by adhering to and inactivating almost all kinds of microorganisms and their toxic products.8,9 It is therefore more likely that the low LDL-C is the culprit, rather than an elevated IL-6. Why low LDL-C causes cancer remains to be elucidated.
References
1. DiNicolantonio JJ, McCarty MF. Is interleukin-6 the link between low LDL cholesterol and increased noncardiovascular mortality in the elderly?. Open Heart 2018;5:e000789. doi:10.1136/openhrt-2018-00078
2. Ravnskov U. Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM 2012;105:383-8.
3. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM 2003;96:927-34.
4. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–90.
5. Burgess S, Timpson NJ, Ebrahim S, Davey Smith G. Mendelian randomization: where are we now and where are we going? Int J Epidemiol 2015;44:379-88. 27.
6. Martinez AN, Mehra S, Kaushal D. Role of interleukin 6 in innate immunity to Mycobacterium tuberculosis infection. J Infect Dis 2013;207:1253-61. doi: 10.1093/infdis/jit037.
7. Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 1989;169:333-8. 26.
8. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 2009;39:3-16.
9. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 2012;344:391-4.
We read with great interest Kaura and colleagues’ evaluation of a multidisciplinary care team for hospital inpatients with infective endocarditis (IE) (1). The study provides further evidence for the effectiveness of a team-based approach to IE care – a model endorsed by both European (2) and American (3) guidelines. Despite limitations inherent in a before-and-after study design, it is clear that the IE team provides patients rapid access to cardiology, microbiology, and surgical care with coordination between services.
Notably absent from this multidisciplinary approach, however, is care for substance use disorders. We wish to draw readers’ attention to the 10% of study participants for whom injection drug use (IDU) was identified as a predisposing factor in their IE. We believe a coordinated IE team offers enormous potential to provide addictions care and harm reduction services for patients with IE who inject drugs.
Compared with people who do not inject drugs, people who inject drugs are far more likely to have recurrences and repeat hospitalizations for IE, and face increased mortality risk after a first episode of IE (4,5). Rates of hospitalization for IDU-associated IE also appear to be increasing (4,6–8).
Evidence-based interventions can be provided in-hospital to reduce both rates of injecting and harms associated with ongoing injection. These interventions include initiating opioid agonist therapies (e.g. methadone or buprenorphine) for opi...
We read with great interest Kaura and colleagues’ evaluation of a multidisciplinary care team for hospital inpatients with infective endocarditis (IE) (1). The study provides further evidence for the effectiveness of a team-based approach to IE care – a model endorsed by both European (2) and American (3) guidelines. Despite limitations inherent in a before-and-after study design, it is clear that the IE team provides patients rapid access to cardiology, microbiology, and surgical care with coordination between services.
Notably absent from this multidisciplinary approach, however, is care for substance use disorders. We wish to draw readers’ attention to the 10% of study participants for whom injection drug use (IDU) was identified as a predisposing factor in their IE. We believe a coordinated IE team offers enormous potential to provide addictions care and harm reduction services for patients with IE who inject drugs.
Compared with people who do not inject drugs, people who inject drugs are far more likely to have recurrences and repeat hospitalizations for IE, and face increased mortality risk after a first episode of IE (4,5). Rates of hospitalization for IDU-associated IE also appear to be increasing (4,6–8).
Evidence-based interventions can be provided in-hospital to reduce both rates of injecting and harms associated with ongoing injection. These interventions include initiating opioid agonist therapies (e.g. methadone or buprenorphine) for opioid use disorders, providing sterile injecting equipment (e.g. needles, syringes, water, cleaning swabs, cookers, and ascorbic acid), and counselling patients on safer injecting practices to reduce risks of infection (9–15).
Hospital admissions for IDU-associated IE represent an opportunity for clinicians to reach patients who are less likely to seek medical attention, and for many patients may provide new motivation to engage in treatment for substance use disorders (16–23). Treatment of acute opioid withdrawal at the time of admission, managing the substance use disorder, and establishing a therapeutic alliance can help to improve adherence to medical management of IE and avoid unplanned discharges against medical advice that often result from active, untreated substance use disorders (10,13,16,18,19,24–31).
Unfortunately, inpatient treatment for IDU-associated IE often focuses on the infection and the medical sequelae without addressing the underlying substance use disorder (9,28,32–35). For example, in a recent study of patients treated for IDU-associated IE at a Boston hospital, only 8% had a plan for opioid agonist therapy at the time of discharge (32).
There are multiple reasons for this implementation gap (28,35). Most physicians do not feel competent in addictions care (36,37). Jurisdictions have different limitations on methadone or buprenorphine prescribing, and institutions may not have clear pathways to identify community-based clinicians to continue prescribing opioid agonist therapy following hospital discharge (38,39). In our institutions (which do not yet have multidisciplinary IE care teams), patients with IE may be admitted or discharged through internal medicine, cardiology, cardiac surgery, or critical care, with ad hoc coordination between those services along with infectious diseases or medical microbiology. Each service may feel that the substance use disorder underlying the IE, and the associated increased risks of recurrence and mortality, are not within their scope of practice and are not the responsibility of their particular discipline (34). Clearly reducing these risks is in the best interests of our patients and our communities – so whose responsibility will it be?
While the European and American endocarditis guidelines do not specify how addiction medicine could fit into multidisciplinary IE care teams, recommendations from the British Heart Valve Society specify that all patients with IE who inject drugs should be offered addictions care (40). National and international IE guidelines should consider injection drug use as an important co-morbidity to address as part of patient-centred IE care.
A coordinated, multidisciplinary care team responsible for all inpatients with IE represents an indispensable opportunity to integrate addiction medicine expertise and offer care for substance use disorders to every patient with IE who injects drugs. An IE team should help facilitate initiation of opioid agonist therapy and promote other harm reduction strategies during hospital admissions in order to reduce the heightened risks of early hospital discharges against medical advice, recurrent infective endocarditis, and mortality. This approach could prolong life and reduce suffering for our patients with IE who inject drugs.
References
1. Kaura A, Byrne J, Fife A, Deshpande R, Baghai M, Gunning M, et al. Inception of the “endocarditis team” is associated with improved survival in patients with infective endocarditis who are managed medically: findings from a before-and-after study. Open Heart. 2017 Dec 1;4(2):e000699.
2. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta J-P, Del Zotti F, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075–128.
3. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017 Jun 20;135(25):e1159–95.
4. Wurcel AG, Anderson JE, Chui KKH, Skinner S, Knox TA, Snydman DR, et al. Increasing Infectious Endocarditis Admissions Among Young People Who Inject Drugs. Open Forum Infect Dis. 2016 Jul 26;3(3).
5. Shrestha NK, Jue J, Hussain ST, Jerry JM, Pettersson GB, Menon V, et al. Injection Drug Use and Outcomes After Surgical Intervention for Infective Endocarditis. Ann Thorac Surg. 2015 Sep 1;100(3):875–82.
6. Ronan MV, Herzig SJ. Hospitalizations Related To Opioid Abuse/Dependence And Associated Serious Infections Increased Sharply, 2002–12. Health Aff (Millwood). 2016 May 1;35(5):832–7.
7. Fleischauer AT. Hospitalizations for Endocarditis and Associated Health Care Costs Among Persons with Diagnosed Drug Dependence — North Carolina, 2010–2015. MMWR Morb Mortal Wkly Rep. 2017;66(22);569–573.
8. Hartman L, Barnes E, Bachmann L, Schafer K, Lovato J, Files DC. Opiate Injection-associated Infective Endocarditis in the Southeastern United States. Am J Med Sci. 2016 Dec 1;352(6):603–8.
9. Serota DP, Kraft CS, Weimer MB. Treating the Symptom but Not the Underlying Disease in Infective Endocarditis: A Teachable Moment. JAMA Intern Med. 2017 Jul 1;177(7):1026-1027.
10. Donroe JH, Holt SR, Tetrault JM. Caring for patients with opioid use disorder in the hospital. CMAJ. 2016 Dec;188(17-18):1232–9.
11. Haber PS, Demirkol A, Lange K, Murnion B. Management of injecting drug users admitted to hospital. The Lancet. 2009;374(9697):1284–93.
12. Schuckit MA. Treatment of Opioid-Use Disorders. Longo DL, editor. N Engl J Med. 2016 Jul 28;375(4):357–68.
13. Sharma M, Lamba W, Cauderella A, Guimond TH, Bayoumi AM. Harm reduction in hospitals. Harm Reduct J. 2017 Jun 5;14:32.
14. Thakarar K, Weinstein ZM, Walley AY. Optimising health and safety of people who inject drugs during transition from acute to outpatient care: narrative review with clinical checklist. Postgrad Med J. 2016 Jun 1;92(1088):356–63.
16. Velez CM, Nicolaidis C, Korthuis PT, Englander H. “It’s been an Experience, a Life Learning Experience”: A Qualitative Study of Hospitalized Patients with Substance Use Disorders. J Gen Intern Med. 2017 Mar;32(3):296–303.
17. Frank MG. Capsule Commentary on Velez et al., “It’s Been an Experience, a Life Learning Experience”: A Qualitative Study of Hospitalized Patients with Substance Use Disorders. J Gen Intern Med. 2017 Mar;32(3):314–314.
18. McNeil R, Small W, Wood E, Kerr T. Hospitals as a “risk environment”: An ethno-epidemiological study of voluntary and involuntary discharge from hospital against medical advice among people who inject drugs. Soc Sci Med. 2014 Mar;105:59–66.
19. McNeil R, Kerr T, Pauly B, Wood E, Small W. Advancing patient-centered care for structurally vulnerable drug-using populations: a qualitative study of the perspectives of people who use drugs regarding the potential integration of harm reduction interventions into hospitals: Hospital-based harm reduction. Addiction. 2016 Apr;111(4):685–94.
20. Pollini RA, O’Toole TP, Ford D, Bigelow G. Does this patient really want treatment? Factors associated with baseline and evolving readiness for change among hospitalized substance using adults interested in treatment. Addict Behav. 2006 Oct;31(10):1904–18.
21. Shanahan CW, Beers D, Alford DP, Brigandi E, Samet JH. A Transitional Opioid Program to Engage Hospitalized Drug Users. J Gen Intern Med. 2010 Aug;25(8):803–8.
22. O’Toole TP, Pollini RA, Ford D, Bigelow G. Physical health as a motivator for substance abuse treatment among medically ill adults: Is it enough to keep them in treatment? J Subst Abuse Treat. 2006 Sep 1;31(2):143–50.
24. Pauly B (Bernie), McCall J, Browne AJ, Parker J, Mollison A. Toward Cultural Safety: Nurse and Patient Perceptions of Illicit Substance Use in a Hospitalized Setting. Adv Nurs Sci. 2015;38(2):121–35.
25. Merrill JO, Rhodes LA, Deyo RA, Marlatt GA, Bradley KA. Mutual Mistrust in the Medical Care of Drug Users. The Keys to the “Narc” Cabinet. J Gen Intern Med. 2002 May;17(5):327–33.
26. Aszalos R, McDuff DR, Weintraub E, Montoya I, Schwartz R. Engaging hospitalized heroin-dependent patients into substance abuse treatment. J Subst Abuse Treat. 1999 Sep;17(1-2):149–58.
27. Lee CS, Liebschutz JM, Anderson BJ, Stein MD. Hospitalized opioid-dependent patients: Exploring predictors of buprenorphine treatment entry and retention after discharge. Am J Addict. 2017 Oct 1;26(7):667–72.
28. Hassamal S, Goldenberg MD, Ishak W, Haglund M, Miotto K, Danovitch I. Overcoming Barriers to Initiating Medication-assisted Treatment for Heroin Use Disorder in a General Medical Hospital: A Case Report and Narrative Literature Review. J Psychiatr Pract. 2017 May;23(3):221–9.
29. Suzuki J. Medication-assisted treatment for hospitalized patients with intravenous-drug-use related infective endocarditis. Am J Addict. 2016 Apr 1;25(3):191–4.
30. Chan ACH, Palepu A, Guh DP, Sun H, Schechter MT, O’shaughnessy MV, et al. HIV-positive Injection Drug Users Who Leave the Hospital Against Medical Advice: The Mitigating Role of Methadone and Social Support. Jaids J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):56–9.
31. Ti L, Milloy M-J, Buxton J, McNeil R, Dobrer S, Hayashi K, et al. Factors Associated with Leaving Hospital against Medical Advice among People Who Use Illicit Drugs in Vancouver, Canada. PLOS ONE. 2015 Oct 28;10(10):e0141594.
32. Rosenthal ES, Karchmer AW, Theisen-Toupal J, Castillo RA, Rowley CF. Suboptimal Addiction Interventions for Patients Hospitalized with Injection Drug Use-Associated Infective Endocarditis. Am J Med. 2016 May;129(5):481–5.
33. Liebschutz JM, Crooks D, Herman D, Anderson B, Tsui J, Meshesha LZ, et al. Buprenorphine Treatment for Hospitalized, Opioid-Dependent Patients: A Randomized Clinical Trial. JAMA Intern Med. 2014 Aug 1;174(8):1369.
34. Fanucchi L, Lofwall MR. Putting Parity into Practice — Integrating Opioid-Use Disorder Treatment into the Hospital Setting. N Engl J Med. 2016 Sep;375(9):811–3.
35. Winetsky D, Weinrieb RM, Perrone J. Expanding Treatment Opportunities for Hospitalized Patients with Opioid Use Disorders. J Hosp Med. 2017 Oct 18;E1–3.
36. Wakeman SE, Pham-Kanter G, Donelan K. Attitudes, practices, and preparedness to care for patients with substance use disorder: Results from a survey of general internists. Subst Abuse. 2016 Oct 1;37(4):635–41.
37. Wakeman SE, Baggett MV, Pham-Kanter G, Campbell EG. Internal medicine residents’ training in substance use disorders: a survey of the quality of instruction and residents’ self-perceived preparedness to diagnose and treat addiction. Subst Abuse. 2013;34(4):363–70.
38. Caldiero RM, Parran TV, Adelman CL, Piche B. Inpatient Initiation of Buprenorphine Maintenance vs. Detoxification: Can Retention of Opioid-Dependent Patients in Outpatient Counseling Be Improved? Am J Addict. 2006 Jan 2;15(1):1–7.
39. Noska A, Mohan A, Wakeman S, Rich J, Boutwell A. Managing Opioid Use Disorder During and After Acute Hospitalization: A Case-Based Review Clarifying Methadone Regulation for Acute Care Settings. J Addict Behav Ther Rehabil. 2015;4(2).
40. Chambers J, Sandoe J, Ray S, Prendergast B, Taggart D, Westaby S, et al. The infective endocarditis team: recommendations from an international working group. Heart. 2014 Apr 1;100(7):524–7.
This was so helpful and easy! Do you have any aricelts on rehab?
DiNicolantonio and McCarty suggest that the inverse association between low cholesterol and mortality in elderly people reflects reverse causality; meaning that the low cholesterol is caused by the disorder being treated.1 One of their arguments is that those whose cholesterol decreases with increasing age die more frequently from cancer and other diseases, compared to those with low cholesterol prior to treatment. However, many studies have shown that low cholesterol may predispose to cancer2 as well as infectious diseases.3 In a previous paper2 we identified nine cohort studies including more than 140,000 individuals, in which cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years.
Show MoreThe authors claim that statin treatment does not increase the risk of cancer based on a meta-analysis of 27 randomised trials published by the Cholesterol Treatment Trialists’ (CTT) Collaborators. But very few statin trials have continued for more than five years, and most carcinogenic chemicals need more time to create cancer. In spite of that cancer appeared significantly more often in three statin trials (2). In two other trials, non-melanoma skin cancer appeared more often and with statistical significance if the figures from the two trials were calculated together (2). Since then the number of non-melanoma skin cancers has not been reported in any trial. Fu...
We read with great interest Kaura and colleagues’ evaluation of a multidisciplinary care team for hospital inpatients with infective endocarditis (IE) (1). The study provides further evidence for the effectiveness of a team-based approach to IE care – a model endorsed by both European (2) and American (3) guidelines. Despite limitations inherent in a before-and-after study design, it is clear that the IE team provides patients rapid access to cardiology, microbiology, and surgical care with coordination between services.
Notably absent from this multidisciplinary approach, however, is care for substance use disorders. We wish to draw readers’ attention to the 10% of study participants for whom injection drug use (IDU) was identified as a predisposing factor in their IE. We believe a coordinated IE team offers enormous potential to provide addictions care and harm reduction services for patients with IE who inject drugs.
Compared with people who do not inject drugs, people who inject drugs are far more likely to have recurrences and repeat hospitalizations for IE, and face increased mortality risk after a first episode of IE (4,5). Rates of hospitalization for IDU-associated IE also appear to be increasing (4,6–8).
Evidence-based interventions can be provided in-hospital to reduce both rates of injecting and harms associated with ongoing injection. These interventions include initiating opioid agonist therapies (e.g. methadone or buprenorphine) for opi...
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