|Year : 2019 | Volume
| Issue : 2 | Page : 68-73
Role of thiamine supplementation in the treatment of patients with heart failure: A double-blind randomized controlled trial
Shamim Iqbal1, Aamir Rashid1, Irfan Bhat2, Jahangir Rashid1, Imran Hafeez1, Ajaz Lone1, Khurshid Iqbal1, Iqbal Dar1
1 Department of Cardiology, SKIMS, Soura, Jammu and Kashmir, India
2 Department of Cardiology, GMC, Srinagar, Jammu and Kashmir, India
|Date of Web Publication||28-Jun-2019|
Dr. Aamir Rashid
House No. 8, LD Colony Rawalpora, Srinagar - 190 005, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Introduction: The role of thiamine supplementation in heart failure (HF) patients has shown conflicting results and has not been adequately studied.
Aims and Objectives: The aim and objective were to determine whether thiamine supplementation will provide clinical, biochemical, and echocardiographic benefit in congestive HF patients.
Materials and Methods: In this single-center, double-blind, prospective randomized controlled trial, HF patients with varied etiology were included. Patients were randomly allocated to 1 week of inpatient double-blind intravenous therapy with either placebo or thiamine. Parameters studied included clinical, Echo left ventricular ejection fraction (LVEF), and thiamine pyrophosphate effect (TPPE) levels before/after treatment. After completion of 1-week treatment, all patients were given oral thiamine and evaluated at the outpatient clinic after 6 weeks.
Results: A total of fifty patients were studied. There was no difference at baseline in mean age (61.4 ± 7.1 vs. 62.4 ± 8.0 years), sex (males 52% vs. 56%), etiology (idiopathic dilated cardiomyopathy 68% vs. 60%, ischemic heart disease 20% vs. 24%), clinical parameters, TPPE levels (16.4 ± 5.2 vs. 16.2 ± 6.5%), and LVEF (28.1% ± 6.7% vs. 28.3% ± 6.6%) in thiamine as compared to placebo group. After 1 week of treatment, there was significant improvement in systolic blood pressure (119.2 ± 18.3 vs. 106.1 ± 18.9 mmHgP < 0.001), diastolic blood pressure (77.4 ± 8.3 vs. 68.2 ± 9.7 mm HgP < 0.001), heart rate (67.0 ± 8.4 vs. 81.9 ± 10.7P < 0.001), weight (66.2 ± 9.5 vs. 71.2 ± 8.2 kgP < 0.001), 3rd-day urine output (1286.0 ± 505.7 ml vs. 750.0 ± 237.2 ml [P < 0.001]), New York Heart Association class (1.6 ± 0.5 vs. 2.1 ± 0.4P < 0.001), LVEF percentage change (7.0 ± 5.2 vs. 0.7% ± 4.7%P < 0.001), and TPPE levels (6.8% ± 1.5% vs. 16.0% ± 6.7%P < 0.001) in thiamine compared with placebo group.
Conclusions: Thiamine supplementation significantly improved clinical and echocardiographic parameters. Thiamine supplementation is cost-effective, is benign, and is easily available with significant clinical benefits.
Keywords: Heart failure, left ventricular ejection fraction, thiamine deficiency
|How to cite this article:|
Iqbal S, Rashid A, Bhat I, Rashid J, Hafeez I, Lone A, Iqbal K, Dar I. Role of thiamine supplementation in the treatment of patients with heart failure: A double-blind randomized controlled trial. Heart India 2019;7:68-73
|How to cite this URL:|
Iqbal S, Rashid A, Bhat I, Rashid J, Hafeez I, Lone A, Iqbal K, Dar I. Role of thiamine supplementation in the treatment of patients with heart failure: A double-blind randomized controlled trial. Heart India [serial online] 2019 [cited 2019 Nov 17];7:68-73. Available from: http://www.heartindia.net/text.asp?2019/7/2/68/261838
| Introduction|| |
Heart failure (HF) is a clinical syndrome in which patients have typical symptoms and signs resulting from an abnormality of cardiac structure, function, or both. HF affects 26 million people worldwide, and the burden of HF in India is about 1% of the population which comes to about 5–10 million people. The rural community has less burden, and an actual survey showed HF prevalence to be 1.2/1000. Indian patients are younger, are sicker, and get less medication as compared to guidelines., The mortality in Indian population is 20%–30% over 6 months (after an episode of acute decompensation). In the Trivandrum Heart Failure Registry, one of the three HF patients died within 1 year of follow-up. The Framingham Heart study showed a median survival of 1.7 years in men and 3.2 years in women and 5-year survival of 25% in men and 38% in women. Although ACE-I/ARBS, b-blockers, aldosterone antagonists, and ICD/CRT devices have improved survival, mortality and morbidity rates still remain high. Thiamine is a water-soluble B-complex vitamin and acts as an essential coenzyme in carbohydrate metabolism. Thiamine deficiency (TD) results in impaired oxygenation of tissues through inhibition of both citric acid cycle and hexose monophosphate shunt. Thiamine uptake and excretion is abnormal in HF patients. Animal models have shown that TD can lead to cardiac dysfunction, hypertrophy, and arrhythmia, without the presence of beri beri. In patients with HF, the incidence of TD ranges from 13% to 98%. Thiamine intake is less in HF patients because of early satiety due to splanchnic congestion and cardiac cachexia. Some dietary thiamine sources may also be high in sodium content and thus are generally avoided by HF patients. In addition, HF patients have increased thiamine requirements as a result of the chronic diuretic use which may promote renal wasting., Given the fact that HF is a prominent feature of TD (beri beri), there is value in studying the role of thiamine in the prevention and management of acute and chronic HF. There also appears to be an increased need for thiamine in the setting of HF, as similar nutritional amounts are inadequate in HF patients compared with controls. Inadequate caloric and protein intake is common in HF patients, and the diets of patients with HF do not contain adequate amounts of thiamine-rich foods., In the Indian context, a study by Doshi et al. on 100 HF patients reported a prevalence of 67%. They defined TD as thiamine levels <0.7 ng/ml. Given the proposed role of TD in HF patients, several small studies have been conducted to examine the clinical utility of thiamine supplementation. From our local population, Sofi et al. showed beneficial effects of thiamine supplementation in HF patients; however, they did not measure thiamine levels and had small sample size. We conducted the present study to assess the thiamine status in a subset of HF patients and also for the assessment of clinical and hemodynamic effects of thiamine repletion in these patients.
Aims and objectives
- To study the efficacy of thiamine treatment in congestive HF (CHF) patients
- To compare the various clinical, biochemical, and echocardiographic parameters between patients of CHF who were put on thiamine treatment and those who were put on placebo treatment.
| Materials and Methods|| |
The study was conducted in the Department of Cardiology, SKIMS, Srinagar, from 2010 to 2012. The number of patients enrolled in this study was 50. It was a single-center, double-blind, randomized controlled trial.
All patients with chronic CHF and New York Heart Association (NYHA) functional class 2–4 due to (i) chronic ischemic heart disease (IHD), (ii) idiopathic dilated cardiomyopathy (DCM), (iii) valvular heart disease, and (iv) atrial fibrillation were included in the study. These patients were admitted in the Cardiology Department from June 2010 onward. The diagnosis of HF was made using Framingham Criteria requiring the presence of two major or one major and two minor criteria.
- Acute myocardial infarction
- Left ventricular ejection fraction (LVEF) >45%
- Recent thiamine or multivitamin supplements
- Identifiable (by history and physical examination) causes of TD (alcoholism or malabsorption).
The study participants were randomly allocated to 1 week of inpatient double-blind intravenous therapy with either placebo or thiamine given as two daily intravenous (IV) doses of either normal saline or 100 mg thiamine HCL. A dose of 100 mg BD was selected as most studies, on HF patients used doses of approximately 200 mg daily orally or IV for a maximum duration of 7 weeks. The recommended treatment dose in thiamine-deficient states, such as Wernicke's encephalopathy, is 50–100 mg daily. Thiamine is poorly absorbed orally with a relative bioavailability of 5.3%. Besides, in HF patients, gut wall edema may further impair absorption, so relatively high doses of thiamine are used in HF patients.
Each patient underwent two-dimensional echocardiographic examination before the intravenous treatment and at the end of inpatient week using a commercially available system.
Thiamine status was evaluated by measuring thiamine pyrophosphate effect (TPPE) on erythrocyte transketolase activity prior to and at the end of the week of intravenous treatment by semi-automatic method adopted by Mount et al. A value of >15% was considered to be thiamine deficit.
In addition to thiamine status, the following clinical parameters were daily assessed for 1 week: blood pressure, heart rate, body weight, and 24-h urinary output.
Further, NYHA class, complete blood count, serum glucose, serum Na+/K+, blood urea, serum creatinine, and urine analysis were compared before and after 1 week of treatment. All patients who were taking drugs 5 days before entering the hospital for the study continued them at the same dosages throughout the full 7 weeks of the study. Other than thiamine, no new drugs were added during the study. After completion of 1 week double-blind treatment, all patients were given oral thiamine 200 mg/day (all other medications held constant) and were evaluated at the outpatient clinic after an additional 6 weeks. Echocardiography was again repeated at this visit. The research protocol was approved by the institutional ethics committee. Each patient gave informed consent before entering the study.
Standard statistical procedures were used to analyze the data. Data were described as mean ± standard deviation and percentages. Intergroup comparison was done by Mann–Whitney U-test, and intra-group variance was measured by Wilcoxon signed rank test at 95% confidence interval (CI).
SPSS 20.0 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp) and Microsoft Excel Software were used for data analysis. P < 0.05 was taken as statistically significant.
| Results|| |
A total of fifty patients were studied. The baseline characteristics are shown in [Table 1]. There was no difference in mean age (61.4 ± 7.1 vs. 62.4 ± 8.0 years) and sex (males 52% vs. 56%) in the thiamine group as compared to placebo group. The etiology of HF in the thiamine group was idiopathic DCM (68%), IHD (20%), and valvular heart disease (12%), whereas in the placebo group, it was 60%, 24%, and 16%, respectively (P = 0.5). There was no significant difference in baseline characteristics (blood pressure, heart rate, weight, urinary output, NYHA Class, LVEF, and TPPE levels) between the two treatment groups as shown in [Table 1]. Further, there were no gross abnormalities in the hemogram, serum chemistry, and urine analysis at baseline and at 1 week in both treatment groups. The percentage of patients who were on >40 mg/day of furosemide was (14/25) 52% in thiamine and (15/25) 60% in placebo group (0.57). The baseline TPPE in the group receiving >40 mg/day of furosemide was significantly higher as compared to those with <40 mg/day of furosemide or who were not receiving any furosemide (18.8% ± 5.1% vs. 15.1% ± 5.1%) (P < 0.001).
The effect on various variable (before and after intragroup) after 1 week in thiamine and placebo group is shown in [Table 2]. There was a statistically significant increase in both systolic and diastolic blood pressure of around 10 mmHg and a statistically significant decrease in heart rate of about 16/min after 1 week of treatment in the thiamine group, whereas there was no significant change after 1 week of treatment in systolic blood pressure, diastolic blood pressure, and heart rate in the placebo group. There was a statistically significant decrease of 3 kg in weight after 1 week of treatment in the thiamine group (baseline 69.4 ± 9.9 kg vs. after 1 week 66.2 ± 9.5 kg, P = 0.001), whereas no significant change occurred in the placebo group (baseline 71.3 ± 8.1 kg vs. after 1 week 71.2 ± 8.2 kg, P = 0.08). There was a statistically significant increase of about 700 ml/day of urinary output in the thiamine group (baseline 580.0 ± 248.3 ml vs. 1286.0 ± 505.7 ml P ≤ 0.001, 3rd day), whereas there was no significant change in the placebo group (baseline 744.0 ± 248.5 ml vs. 750.0 ± 237.2 ml, 3rd day.) There was a significant improvement in NYHA Class from 2.2 to 1.6 in thiamine group, whereas no significant change occurred in the placebo group (Thiamine baseline NYHA class 2.2+- 0.4 vs 1.6+-0.5 at 1 week P <0.001 vs Placebo baseline 2.2+-0.4 vs 2.1+-0.4 at 1week). LVEF significantly increased from baseline (28.1% ± 6.7%) to 1 week (30.1% ± 7.5%) and 7 weeks (33.3% ± 8.2%) in thiamine group, whereas in placebo group, there was no significant change from baseline (28.3% ± 6.6%) to 1 week (28.4% ±6.2%), whereas at 7 weeks (33.7% ±7.5%), there was a significant increase in LVEF. There was a significant decrease in TPPE in thiamine group from 16.4% to 6.8% (P < 0.001) at 1 week, whereas in the placebo group, there was no significant change at 1 week (16.2% ± 6.5% to 16.0% ± 6.7%).
|Table 2: Variables before and after treatment in thiamine and placebo groups (intragroup comparison)|
Click here to view
The comparison (intergroup) of various variables in thiamine versus placebo group is shown in [Table 3]. After 1 week of treatment, there was significant improvement in systolic blood pressure (119.2 ± 18.3 vs. 106.1 ± 18.9 mmHg, P < 0.001), diastolic blood pressure (77.4 ± 8.3 vs. 68.2 ± 9.7 mmHg, P < 0.001), heart rate (67.0 ± 8.4 vs. 81.9 ± 10.7, P < 0.001), weight (66.2 ± 9.5 vs. 71.2 ± 8.2 kg, P < 0.001), 3rd-day urine output (1286.0 ± 505.7 ml vs. 750.0 ± 237.2 ml [P < 0.001]), NYHA class (1.6 ± 0.5 vs. 2.1 ± 0.4, P < 0.001), LVEF percentage change (7.0 ± 5.2 vs. 0.7 ± 4.7%, P < 0.001), and TPPE levels (6.8% ± 1.5% vs. 16.0% ± 6.7%, P < 0.001) in thiamine group compared to placebo group. There was a statistically significant 7% increase in LVEF in thiamine group compared to 0.7% in placebo (P < 0.001) at 1 week, whereas at 7 weeks after giving oral thiamine for 6 weeks in both treatment arms, there was an increase of 18.4% ± 9.0% and 19.4% ± 7.2% in LVEF in the thiamine and placebo groups, respectively (P = 0.47).
|Table 3: Comparison of variables between thiamine and placebo groups at 1 week (intergroup comparison)|
Click here to view
| Discussion|| |
In this hospital-based study, HF patients with diverse etiologies were recruited for evaluation of thiamine status and the role of thiamine in the amelioration of symptoms and the impact on various clinical and laboratory parameters. The total number of patients recruited was 50, out of which half were randomized to thiamine replacement and the other half to placebo treatment. There was no significant difference in age, sex, and other baseline characteristics between the two groups. Although TD appears to be present in HF patients., determining the true prevalence of TD in HF patients has been difficult due to variations in disease definitions and testing methods. TD prevalence in HF patients ranges from 3% to 91%,,, with 3% to 27%, in ambulatory setting and 5% to 91%, in hospital setting. The variations in prevalence are possibly due to study location, variable testing standards, small study size, disease severity, food habits, age, use of furosemide, and co-morbid conditions. We found significantly high TPPE (18.8% ± 5.1%) in the subgroup on furosemide with a dose of >40 mg/day, which could be due to inadequate thiamine intake due to furosemide-induced anorexia, decreased intestinal thiamine absorption, impaired cellular thiamine uptake, and utilization due to furosemide-induced hyponatremia and furosemide-enhanced urinary thiamine excretion.
In the thiamine treatment group, both the systolic and diastolic blood pressures increased by an average of 10 mmHg and the heart rate decreased by an average of 16 beats/min (both statistically significant), whereas there were no significant changes in these parameters in the group receiving placebo treatment. This is consistent with other studies., The increase in the systolic and diastolic blood pressures after thiamine replacement is attributed to closing of arteriovenous shunts and temporary volume overload. Moreover, the decrease in heart rate is attributed to mild peripheral vasodilator effect of thiamine in the failing heart. In the thiamine treatment group, there was a statistically significant decrease of about 3 kg of weight after 1 week of treatment and significant increase of about 700 ml/day urinary output on the 3rd day of treatment, which is attributed to the natriuretic effect of thiamine. Seligmann et al. demonstrated a mean increase of urinary output of 500 ml/24 h with an average weight loss of 1 kg in thiamine-treated group. Brisk diuresis was similarly shown by Shimon et al. in their thiamine-treated cohort of HF patients. There was a statistically significant increase of about 7% increase in LVEF at 1 week in the thiamine treatment group, whereas no significant change was demonstrated in the LVEF of placebo treatment group at 1 week. This correspondingly translated into improvement in functional class from mean NYHA class 2.2–1.6 (P < 0.001) in the thiamine group. After 6 weeks of oral thiamine replacement in both treatment arms, there was about 20% increase in LVEF in both the groups. This was a significant finding because an increase in ejection fraction has been associated with a favorable effect on survival in patients with CHF. Thiamine-deficient heart disease is characterized by sodium and water retention, peripheral vasodilation, and myocardial failure; as a result, TD is presumed to worsen symptoms in the setting of established CHF. Inhibition of pyruvate dehydrogenase complex is the presumed mechanism by which TD exacerbates HF. Inhibitions of pyruvate dehydrogenase complex have been postulated to decrease the efficiency of adenosine triphosphate production, cellular acidosis, and increased fatty acid levels. The improvement in LVEF after thiamine replacement has been consistently demonstrated in other studies., Shimon et al. demonstrated an increase in LVEF of 22% in 27 patients of HF who were put on 6 weeks of oral thiamine treatment in their study. In our study, the improvement in LVEF in both the subgroups after 6 weeks of oral thiamine reinforces the role of thiamine in correcting the underlying subclinical TD because no change in any other medication was made during the entire study period. However, thiamine pyrophosphate has been shown to have beneficial hemodynamic effects and to improve myocardial energy balance in experimental myocardial infarction and ischemic cardiac arrest in the absence of preceding TD.
The improvement seen in our patients may have been either due to improved contractile function or a diuretic response to thiamine. Regardless of the mechanism of the effect, the end result of thiamine administration in our study was improved myocardial function and functional class. There was a significant decrease in TPPE in thiamine-treated group from 16.4% to 6.8% (P < 0.001) after 1 week of treatment, but there was no significant change in TPPE at 1 week in the placebo group, and the change in TPPE at 1 week in thiamine group was statistically significant compared to placebo group (P < 0.001). Because the baseline TPPE was similar in both treatment arms, it implies that there was subclinical TD which got corrected in the thiamine treatment group. The TD in HF patients has been observed by Hanninen et al., Seligmann et al., and Shimon et al. in their studies; however, the patient cohort enrolled in these studies were on high-dose diuretics. Yui et al. first described increased losses of thiamine secondary to loop diuretic therapy. Since then, several other studies, have replicated these findings suggesting that loop diuretic therapy can lead to TD, mainly secondary to hyperexcretion. The clinical improvement experienced by our patients after thiamine supplementation and ensuing normalization of the TPPE was associated with objective evidence of improved cardiac contractility. As no other change was made in the patients' therapeutic regimen, it is possible to ascribe the clinical improvement to the correction of TD. In a meta-analysis done by Dinicolantonio et al., thiamine supplementation resulted in a significantly improved net change in LVEF (3.28%, 95% CI: 0.64%, 5.93%) compared with placebo. A recent meta-analysis by Jain et al. included nine studies and reported that TD is more common in HF patients than controls (odds ratio 2.53, 95% CI 1.65–3.87). Diuretic use, changes in dietary habits, altered thiamine absorption, and metabolism were identified as possible mechanisms of TD in HF patients. They concluded that small observational studies and randomized controlled trials suggest that thiamine supplementation in HF improve ejection fraction and reduce symptoms. However, our clinical observation needs to be confirmed by a large-scale, placebo-controlled, double-blind study.
This was a single-center study with small sample size; however, it was higher than other studies which have studied thiamine supplementation. Longer follow-up is required to fully ascertain the beneficial effect of thiamine supplementation.
| Conclusions|| |
Thiamine supplementation significantly improved clinical and echocardiographic parameters in HF patients. The cost and risks of thiamine supplementation are minimal. Thiamine supplementation should be considered in HF patients although larger studies are needed to fully ascertain its benefit.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]