2 Minute Medicine Rewind March 1, 2021

Diagnosis and treatment of iron deficiency in heart failure: OFICSel study by the French Heart Failure Working Group

1. Cardiologists were under-testing, against guidelines, for iron deficiency in heart failure patients, likely resulting in under-diagnosing and under-treatment.

Evidence Rating Level: 2 (Good)

One in every two patients with heart failure (HF) also has iron deficiency (ID). Iron supplementation can improve both quality of life and exercise capacity in these patients; according to a recent French analysis, by reducing hospitalizations, iron supplement may even  save costs to their national health insurance. The European Society of Cardiology (ESC) guidelines recommend diagnostic testing for iron deficiency in patients newly diagnosed with HF and during follow-up, and only recommends intravenous iron supplementation for patients with HF with reduced ejection fraction (HFrEF) diagnosed with ID. However, little is known about how these guidelines are implemented in clinical practice. In this French observational, transversal multicentre trial, data from 2822 patients, who were hospitalized at least once for HF in the last five years , and 300 cardiologists was collected. These patients (median age of 69 years, 69.3% male) included both inpatients and outpatients with acute and chronic heart failure. In total, only 38.1% of patients were tested, and 33.9% were diagnosed with ID. Of those diagnosed, 46.2% received iron supplementation (76.2% intravenously, 23.8% orally). In patients with HFrEF diagnosed with iron deficiency, only 39.3% received intravenous iron supplementation as per ESC guidelines. Patients who were tested for ID were more likely to have ischaemic heart disease (p=0.027), were younger (67 vs 69 years, p=0.0002), and were less frequently smokers (p=0.035), compared to patients who were not tested. However, between these two groups, there were no differences in median left ventricular ejection fraction (LVEF), time since last decompensation, or a diagnosis of HF within the last three months. Meanwhile, those patients who were diagnosed with ID were more likely older, women, had a higher median LVEF, and ischaemic heart disease than patients without iron deficiency. Moreover, patients with iron deficiency were also more likely to have more HF disease, having higher rates of NYHA class III or IV, acute HF, shorter intervals from their last decompensation, and increased diuretic use. Limitations of this study may include selection bias by design, with this population being ten years younger on average and receiving more optimal treatment than most published HF registers. Nonetheless, cardiologists should be encouraged to follow ESC guidelines on ID testing and iron supplementation to optimally treat their HF patients.


Twelve-month effects of everolimus on renal and lung function in lung transplantation: differences in chronic lung allograft dysfunction phenotypes

1. Lung transplant patients showed improved renal function and reduced immunosuppressant dosage after twelve months of everolimus treatment.

2. Patients with chronic lung allograft dysfunction showed either sustained or worsened lung function depending on phenotype.

Evidence Rating Level: 2 (Good)

Following a lung transplant, two factors which reduce survival are graft failure and chronic lung allograft dysfunction (CLAD). CLAD is a substantial (> 20%) and persistent decline from baseline in measured forced expiratory volume in the first second (FEV1). CLAD can present as two phenotypes, bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Everolimus is a maintenance immunosuppressant recently introduced to lung transplant patients to prevent CLAD with its antiproliferative properties. Due to its antifibrotic effects, everolimus has been shown to slow progression of both BOS and RAS. However, use of everolimus and its impact on renal and pulmonary function as well as mortality in both CLAD and non-CLAD patients has yet to be compared beyond 6 months. In this retrospective trial, renal and lung function of 26 patients with lung transplants treated with and/or switched to everolimus were monitored for 12 months. 17 patients had CLAD (10 BOS, 7 RAS), and in all patients, reduction in immunosuppressant dosage (ISD) and all-cause mortality rate were tracked. Overall, patients experienced improvement in renal function (serum creatinine -17%, estimated glomerular filtration rate +24%) and stabilization in pulmonary function (FEV1 -0.5%, forced vital capacity (FVC) +0.05%). While RAS patients, which typically have a worse prognosis, underwent progressive functional loss, BOS patients experienced a gradual increase in FEV1 and FVC stability. When comparing functional trends between CLAD and nonCLAD patients, the only significant difference occurred in the 12th month; FEV1 and FVC increased progressively. This resulting significant FVC% change is most likely due to the ameliorative effects of everolimus on renal function as opposed to direct pulmonary benefit. Finally, with the introduction of everolimus, all patients also experienced a significant and persistent ISD reduction (mean 37.7% reduction from baseline). While by design, this observational study cannot determine causation,  these results demonstrated the functional trends of improving renal function and reduced ISD in both CAD and non-CAD patients with lung transplants after treatment with everolimus. Despite everolimus introduction, CLAD patients continued to show declining pulmonary function, with the worst trend in RAS and with BOS identified as an “early everolimus responsive phenotype.” Ultimately, further study through conducting randomized, controlled trials with larger sample sizes are needed to support these trends.


Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

1. In patients who previously discontinued statin treatment due to muscle symptoms, there was no significant difference in reported mean muscle symptoms between daily atorvastatin 20 mg and placebo.

Evidence Rating Level:1 (Excellent)

While statins have been shown to reduce cardiovascular disease events in primary and secondary events when indicated,  unblinded observational studies and media reports have reinforced the belief statins frequently cause muscle pain. As a result, many patients discontinue treatment, increasing their morbidity and mortality from cardiovascular disease. In clinical care, it can be difficult for both the clinician and patient to ascertain whether muscle symptoms are caused by statin treatment or not. In StatinWISE, a series of randomised, double-blinded, placebo-controlled, n-of-1 trials, 200 participants who had recently stopped their statin treatment due to muscle symptoms were randomised to a sequence of six, two-month treatment periods of either atorvastatin 20 mg daily or placebo. Participants were asked to rate their muscle symptoms on a visual analogue scale (0-10) at the end of each treatment period, and symptom scores from statin and placebo periods were compared. From 151 participants who provided symptom scores for at least one statin and one placebo period, no significant difference was found in mean muscle symptom score between statin and placebo treatment (mean difference statin minus placebo -0.11, p=0.40). Moreover, the observed mean muscle symptom score was lower during statin treatment periods than placebo. With 9% and 7% of patients withdrawing during statin and placebo treatment respectively, there was also no significant difference in withdrawals (of consent, from muscle symptoms, unknown) between the two treatment period types. Moreover, two out of three participants restarted long-term statin treatment. To note, participants contributed different numbers of periods for analysis, resulting in an estimated treatment effect that is not identical to the crude difference in means; nonetheless, neither are statistically significant. Furthermore, from the patients who withdrew secondary to intolerable muscle symptoms, lab test data, such as for creatine kinase, were not collected. Nevertheless, this study showed a lack of overall effect of statin treatment on muscle symptoms in patients who previously discontinued treatment due to severe muscle symptoms. These results support the continued use of n-of-1 trials to further investigate whether muscle symptoms may be associated with statins at higher doses or as a tool in clinical care to explore other transient adverse events associated with other medications.


Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study

1. Polypharmacy in non-care home residents was strongly associated with higher rates of severe COVID-19.

Evidence Rating Level: 3 (Average)

Resistant hypertension, which is uncontrolled despite maximal medical therapy, affects up to 10% of patients diagnosed with hypertension. Renal artery denervation has been demonstrated in a number of smaller, nonrandomized and/or unblinded studies to significantly reduce blood pressure in patients with resistant hypertension. In ongoing discussions about medication use that increased risk of experiencing severe disease from COVID-19, drugs acting on the renin-angiotensin system as well as those associated with an increased risk of community-acquired pneumonia were suggested. A recent review published a list of 17 widely prescribed drug classes associated with increased pneumonia risk, described as “medications compromising COVID”. An initial analysis of REACT-SCOT reported a strong association of severe COVID-19 with the dispensing of at least one prescription in the last year; this study aimed to investigate which drug classes may be responsible for this association. In this randomized controlled, pharmaceutical-sponsored trial, 535 patients were randomized in a 2:1 ratio to receive catheter-based radiofrequency renal artery denervation or a sham procedure (renal angiography only) to study the effect on participants’ office systolic blood pressure at 6 months compared to their baseline, with a superiority margin of 5mmHg. In this matched case-control study, all 4251 severe cases of COVID-19 in Scotland were matched to 36 378 controls from the Community Health Index database for age, sex, and same primary care practice. Records from hospital discharges since 2015 and prescriptions issued within the last 240 days were analysed. Results showed a strong association between the rate of severe COVID-19 and the number of classes of non-cardiovascular drugs dispensed. This association was restricted to patients who were not care home residents, with a rate ratio of 10.89 (95% CI 7.7-13.3) between COVID-19 and dispensing of 12 or more drug classes over those with no prescriptions; this association was also stronger in those under 75 years of age and/or without any conditions known to confer vulnerability to COVID-19. Interestingly, this trend decreased with the number of cardiovascular drug classes dispensed. All 17 drug classes listed as “medications compromising COVID” were associated with an increased risk of COVID-19.  A multivariable regression showed the strongest independent associations were with antipsychotic drugs (RR 4.18 (95% CI 3.42-4.11), proton pump inhibitors (at 2 defined daily doses/day, RR 2.2 (95% CI 1.72-2.83)), and opioid analgesics (for 50 mg morphine equivalents/day, RR 3.66 (2.68-5.01)), as well as with gabapentinoids and antihistamines.These associations persisted after adjustment for covariates and were stronger with more recent exposure. To note, data on severity of comorbidities of these patients and no morbidity data from primary care, such as on health behaviours like smoking, could be collected. Nonetheless, these results found associations with severe COVID-19 and polypharmacy, namely drugs likely to cause sedation, respiratory depression, dyskinesias, anticholinergic effects, and/or affect the gastrointestinal tract. Guidance on reducing overprescribing and generally inappropriate pharmacy should be reinforced.


Association of Angiotensin‐Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with the risk of hospitalization and death in hypertensive patients with Coronavirus Disease‐19

1. There is no association between ACE inhibitor or ARB use compared with other antihypertensives for risk of COVID-19 hospitalization for outpatients.

2. There is no association between ACE inhibitor or ARB use compared with other antihypertensives for increased mortality risk in patients hospitalized with diagnosis of COVID-19.

Evidence Rating Level: 2 (Good)

Ever since the role of the ACE2 receptor was implicated with the role of viral infection at the beginning of the pandemic, the relationship between angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) with the rate and severity of coronavirus disease-19 (COVID-19) infection has been under study. While most studies show that ACE inhibitor and ARB use do not have an effect on COVID-19 hospitalization, many of these have poor or inappropriate study design, including showing results without adjusting for confounding variables, lacking a comparator, and a lack of long-term follow-up. In this retrospective cohort study, there were two separate sub-studies looking at either outpatients or inpatients using information from public insurance (Medicare Advantage) and private insurance databases. Both models used extensive propensity score matching to adjust for confounders. In the outpatient study, 2263 individuals who had a diagnosis of hypertension and used hypertensive medications (as defined as first- or second-line agents by the American Heart Association guidelines) in the year 2019 and had a positive COVID-19 test as an outpatient between March 6, 2020 to May 3, 2020 were included. For the outpatient study, there was no association of ACE inhibitors (HR 0.77, CI 0.52-1.13, p=0.18) or ARBs (HR 0.88, CI 0.61-1.26, p=0.48) with hospitalization compared to other antihypertensive medications. When comparing providers, ACE inhibitors were associated with a lower hospitalization risk in older public insurance compared to the younger private insurance group (HR 0.61, CI 0.41-0.93, p=0.02 vs. HR 2.14, CI 0.85-5.60, p=0.12). In the inpatient study, there was also no association of ACE inhibitor or ARB use for in-hospital mortality (HR 0.97, CI 0.81-1.16, p=0.74 and HR 1.15, CI 0.95-1.38, p=0.15) compared to other antihypertensive medications. Strengths of this study include extensive analysis for confounding, a large sample size, and longer follow-up. Limitations include that the proportion of patients with sufficient data to be included in the propensity matched groups was smaller than the original population. There was also some uncertainty in whether medication was continued or discontinued during acute illness and whether that impacted patient outcomes; neither will all individuals necessarily seek care despite having symptoms. These results further enforce that there is no association of the use of these antihypertensive medications to increased risk of contracting COVID-19 or having higher mortality. These results also discourage ACE inhibitor or ARB use as prophylaxis against severe disease.

Image: PD

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