Tranexamic Acid and GI Bleeding

Tranexamic acid is often used to reduce bleeding, particularly after surgery and may reduce bleeding-related death in patients with trauma. It remains unclear if tranexamic acid reduces deaths in patients who present with acute GI bleeding.

An international, multicenter, randomized, placebo-controlled trial examined this question. Adult patients with acute GI bleeding were randomly assigned to either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). The primary outcome was death due to bleeding within 5 days of randomization. 12 009 patients were randomly allocated to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%).

Death due to bleeding within 5 days of randomization occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82-1·18).

Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39).

Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).

In other words, this large clinical trial showed that tranexamic acid did not reduce death from gastrointestinal bleeding but may result in higher venous thromboembolic events. Thus, IV tranexamic acid is not useful in patients with acute GI bleeding.

ACE2 May be a Receptor for COVID-19 Virus Entry into the Cells

Because SARS-COV virus has significant similarities to the COVID-19 virus (also called SARS-CoV-2), it is worth comparing the two viruses for similarities to learn about COVID-19.

SARS-CoV has surface spikes that bind to Angiotensin Converting Enzyme 2 (ACE2) and gain entry into human cells. Once inside the human cell, virus downregulates the further expression of ACE2 on cell surface. Importantly, ACE2 surface expression is important to keep inflammatory response in check and low levels of ACE2 results in increased inflammatory response.

It is quite likely that COVID-19 (SARS-CoV-2) also binds to ACE2 receptors. In fact, there is significant homology in the amino acid and gene sequence of virus spikes. Further, the computer-generated 3-D models show similar structure and maintenance of the binding site.

Thus, one can propose a model similar to SARS-CoV where COVID-19 binds to the ACE2 on surface of pulmonary epithelial cells, downregulates these receptors, worsens local inflammatory responses and leads to the lung disease that we see on lung imaging (particularly on CT scans) that is so prevalent in these patients.

Of note, ACE2 is present on the intestinal epithelial cells luminal surface giving another portal of entry for these patients and presence of diarrhea in some patients with COVID-19. Other places where ACE2 expression is particularly high include heart, kidneys, and testes.

While there are several inhibitors of ACE1 in the market and are one of the most commonly prescribed medications for hypertension, these inhibitors don’t work on ACE2. Further, inhibition of ACE2 might potentially lead to worsening of the disease in these patients.

Other methods that can be tested include vaccinations against the viral spike proteins, inhibition of ACE2 downstream pathways such as TMPRSS2, and delivering excessive amounts of ACE2 (or homologues) to saturate viral surface receptors.

The role of ACE2 as potential anti-inflammatory agent in human body makes developing any vaccine or therapeutic drugs challenging as it is difficult to predict the responses inside our bodies. Because ACE2 pathways are not fully discovered yet, the development of effective treatments with minimal adverse effects likely will be challenging.

Hydrate or not to Hydrate that is the Question

A large amount of previous evidence have suggested that hydration of patients undergoing an intravenous contrast study reduces the risk of kidney injury. However, recently some data suggests that the contrast induced injury may simply be because patients who are undergoing emergent intravenous contrast study are sicker patients and are likely to develop kidney injury irrespective of getting contrast.

Timal and colleagues conducted a randomized controlled trial enrolling 523 patients with stage 2 chronic kidney disease and found that there was no benefit of giving intravenous fluids to patients who were getting intravenous contrast. The study details are here

Another Drug (Interferon beta-1A) is Found to be Ineffective in Patients with Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening disease. It is characterized by leaky lungs blood vessels resulting in fluid in the lungs (pulmonary edema) which results in low oxygenation of the blood flowing through lungs. Usually, there is an underlying severe disease, often sepsis, that results in ARDS. Currently, the treatment of patients with ARDS is treatment of the underlying cause and supportive care with a hope that lungs will recover on their own.

The main mechanisms underlying underlying ARDS is an uncontrolled inflammatory response resulting in injury to the walls of the lung blood vessels leading to increased leakage of fluids into the lung alveoli. Interferon beta-1A (IBA) has been shown to reduce leakage from blood vessels and dampen inflammatory response. An early study showed some benefit.

A recently reported randomized controlled trial found no benefit of the drug. Investigators did not find any benefit with regard to ventilator free days or 28-day mortality. In fact, if anything, significant number of patients suffered adverse effects. While the study was not effective in showing a benefit, it raised important question about possibility of other therapies affecting the beneficial effect of this drug. In conclusion, more research is needed for this disease for which we have no therapies available.

The Saga of Vitamin C and Septic Shock

Vitamin C has been proposed as a drug that may help patients with sepsis due to its antioxidant effects. Earlier studies have been inconclusive. Another randomized trial was reported this week. Investigators wanted to examine if the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.

This was a multicenter studies conducted in 10 ICU in Australia, New Zealand, and Brazil. The study was open label (treating physicians were aware of the therapy), randomized (patients were allocated to the treatment or control arm randomly) clinical trial.  Investigators recruited 216 patients fulfilling the Sepsis-3 definition of septic shock.

Patients in the vitamin C arm (n = 109) received intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours). Patients in the control arm (n = 107) received only intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.

Median time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was –0.6 hours (95% CI, –8.3 to 7.2 hours; P = .83). Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.

The findings strengthen the clinical data, which is in contrast to the basic science data, that vitamin C may have clinical benefit in septic patients. At the minimum, the study findings suggest that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. For some, this might be end of vitamin C story, others may still want to examine vitamin C potential little more.

Vitamin D, Calcium Supplementation, and Bone Fracture Risk

Osteoporosis can be considered an aging process. In a lifetime, osteoporotic fracture affects about 1 in 2 women and 1 in 5 men aged 50 years or older with hip fracture being the most serious type of osteoporotic fracture. Vitamin D is essential for optimal musculoskeletal health because it promotes calcium absorption, mineralization of bone, and maintenance of muscle function. Vitamin D supplementation in several observational studies have been shown to decrease the risk of fracture. Similarly, calcium supplementation has also been shown to be preventive. However, results from the randomized clinical trials, the gold standard for determining if a given therapy is effective or not are lacking.

Yao and colleagues published a systematic review and meta-analysis and pooled data from large observation studies and randomized clinical trials to answer some key questions. In particular, they wanted to assess the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. To identify relevant studies, they searched several medical literature databases: PubMed, EMBASE, Cochrane Library, and other randomized controlled trial databases. The search was from the start of database until December 31, 2018. They selected observational studies involving at least 200 fracture cases and randomized clinical trials enrolling at least 500 participants and reporting at least 10 incident fractures were included.

They identified 11 observational studies with a total number of 39 141 participants who had total of 6278 fractures, out of which 2367 were hip fractures. When they pooled the study results, they found that each increase of 10.0 ng/mL (ie, 25 nmol/L) in vitamin D was associated with an adjusted rate ratio for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted rate ratio for hip fracture of 0.80 (95% CI, 0.75-0.86).

They also identified 11 RCTs of vitamin D supplementation alone enrolling 34 243 participants, 2843 fractures of which 740 were hip fractures. These trials did not find any decrease in risk of any fracture with Vitamin D supplementation alone (rate ratio, 1.06; 95% CI, 0.98-1.14). Similarly, there was no decrease in risk of hip fracture (rate ratio, 1.14; 95% CI, 0.98-1.32).

In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with daily vitamin D (daily doses of 400-800 IU) and daily calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (rate ratio, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (rate ratio, 0.84; 95% CI, 0.72-0.97).

The final word: If you take vitamin D and/or calcium to reduce the risk of osteoporosis and osteoporotic fractures, you should take both calcium and vitamin D supplements together. Taking just one medication is unlikely to decrease fracture risk.

Fragility Index for Randomized Controlled Trials

An interesting question – how ‘fragile’ are the results of a randomized controlled trial (RCT)?

RCTs are gold-standard for determining the efficacy of a treatment. RCTs randomly assigned patients to an intervention arm or to a placebo (or standard of care or active treatment) arm. Because patients are randomly assigned, we expect that all patient characteristics (genetic, environmental etc.) would be balanced in the two groups. RCTs are often published with significant results – small RCTs without significant results are generally either not published or published in low-tier journals and don’t get prominence

Even when we randomly assign patients to a treatment arm or control arm, there is always a possibility that the two arm may be imbalanced by chance on measured or unmeasured variables. Further, it is also possible that just by chance one group may have statistically significant result than the other group without any true benefit (or harm) of the treatment. While we generally use a p-value of less than 0.05 (which says that there is a 1 in 20 probability that the results are observed due to chance only – not the right definition but its simple!), there remains a small chance that results will be not significant.

In comes ‘Fragility Index’, a measure of determining the robustness of results. Fragility index is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. The fragility index is an easy to calculate index that provides an intuitive way to understand the precision of trial results. Knowing the fragility index and comparing it to the number of patients lost to follow-up can help to understand the uncertainty in evidence even when a study has positive results.

Khan et al, examined cardiovascular clinical trials published between 2007-17 in major Cardiology journals. All trials were large with >500 patient enrollment. Among the 123 RCTs the median fragility index was 13.In almost 1/3rd of trials, the number of patients lost to follow-up was more than the fragility index.

In another study Gaudino et al examined the clinical trials used to support evidence in cardiology guidelines and determined the fragility index. They found that more than a quarter of RCTs supporting current guidelines on myocardial revascularization have a fragility index 3 or lower. Further over 40% of trials had a fragility index which was lower than the number of patients lost to follow-up.

Vasodilatation in Acute Heart Failure

Acute heart failure is a condition when the cardiac output (the amount of blood pumped by heart every minutes) is not sufficient to meet the needs of the body. Cardiac output depends on how much blood is in the heart before it starts contracting (cardiac pre-load), how strongly hear contracts (cardiac contractility), how much resistance heart faces when pumping blood into the arteries (cardiac after-load, or peripheral vasoconstriction), and how many times heart beats in a minutes.

For a failing heart, increasing the force of contraction and decreasing the pressure against which it pumps blood (after-load or vasoconstriction) are important factors. In fact, peripheral vasodilators such as ACE inhibitors or ARB are standards of care for heart failure patients. One may ask, what if we decrease the pressure against which heart pumps blood really low, in other words, if we cause high (intensive) vasodilation with drugs. This particular hypothesis was tested in The GALACTIC Study recently published in JAMA.

Interestingly, authors found no benefit of intensive vasodilatation on composite endpoint of death or rehospitalization. Further, the intensive vasodilation arm had higher risk of adverse effects such as worsening renal function, hypokalemia, dizziness, and hypotension.

The results are important because they suggest that while we focus on cardiac output, blood flow to individual organ (or fraction of cardiac output received by various organs may be as important, if not more important. Intensive vasodilatation likely results in poor perfusion to various organ resulting in increased adverse effects.

Should Older Patients with Subclinical Hypothyroidism be Treated with Thyroid Replacement?

With increasing age, many patients develop subclinical hypothyroidism. Subclinical hypothyroidism is defined by the presence of elevated thyroid stimulating hormone (TSH) but normal free T4 levels. Some patients with subclinical hypothyroidism also have symptoms that are not uncommon with increasing age such as constipation, tiredness, mental slowness, and fatigue.

Prior studies have found no association between treating patients with subclinical hypothyroidism with thyroid replacement therapy and resolution of symptoms. However, very old individuals (older than 80 years) are often not included in the studies.

To examine if treatment of subclinical hypothyroidism with thyroid replacement therapy results in resolution of such symptoms, Moojiraat et al. combined data from two randomized controlled trials. Combining data from two trials results in increased number of patients above 80 (and hence power of the study to detect a difference).

Contrary to expectations, but consistent with previous findings, thyroid replacement therapy does not result in resolution of symptoms in patients with subclinical hypothyroidism. Instead, there may be some increase in adverse events.

Angiotensin Receptor Blockers and Suicide Risk

Interesting conclusions in a study reported in the JAMA Network Open:

The use of ARBs may be associated with an increased risk of suicide compared with ACEIs.

Investigators matched 964 cases to 3856 controls. Compared to ACE inhibitors, ARBs were associated with 63% higher risk of death by suicide. The results remained significant (60% increase) when individuals with history of self-harm were excluded.

Direct Oral Anticoagulants vs Warfarin in Older Patients With Atrial Fibrillation and Ischemic Stroke

This observational study examined 11,662 patients with atrial fibrillation who had had an ischemic stroke and were anticoagulation naïve, patients discharged while receiving:

1. Direct oral anticoagulants (DOACs) had more days at home post-discharge
2. Were less likely to experience major adverse cardiovascular events, all-cause mortality, all-cause readmissions, cardiovascular readmissions, or hemorrhagic strokes
3. Had a small but significant increase in gastrointestinal bleeding.

Overall, DOACs appear to be an effective and safe treatment option compared with warfarin for patients with atrial fibrillation who have ischemic stroke and may be even more beneficial despite a small in crease in gastrointestinal bleeding.

Perioperative Direct Oral Anticoagulant Use

This study of 3007 patients with atrial fibrillation who were undergoing surgery enrolled patients to have:

1. Direct Oral Anticoagulants (DOACs) were omitted 1-day before a low-bleeding-risk procedure
2. DOACs were omitted 2 days before a high-bleeding-risk procedure
3. Patients with renal impairment had the pre-operative omission duration readjusted

Study investigators found that the perioperative risk of bleeding and arterial thromboembolism were low with this simplified strategy. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort.

DOACs	Bleeding Risk	Arterial Thromboembolism
Apixaban	1.35	0.16
Dabigatran	0.90	0.60
Rivaroxaban	1.85	0.37

Anti-platelet Drugs after Coronary Intervention

The type and duration of anti-platelet therapy after cardiac catheterization and stent placement (also called percutaneous coronary intervention or PCI) is an ongoing debate.

There are two main groups of drugs. One is aspirin which is under use for over 100 years and we know a lot about it. The other group is P2Y12 blockers. P2Y12 is a receptor on the surface of platelets and these drugs block this receptor. The most well-known drug in this group is clopidogrel or Plavix.

A Japanese study examined the role of aspirin + clopidogrel for one month followed by 12-months of clopidogrel versus aspirin + clopidogrel for 12 months showed that the earlier strategy was superior. In contrast, a Korean study, also published in JAMA, found that there is no statistically significant difference between the two.

The results may appear different and the reason my be that the two studies were somewhat different. Below are some of the differences:

1. Korean study allowed the use of other P2Y12 inhibitors/blockers such as prasugrel or ticagrelor while Japanese study allowed on clopidogrel.

2. Korean study had lower adherence to drug therapy in the P2Y12 group as compared to combined group (79% vs. 95%).

3. P2Y12 inhibitors were given for 3-months in the first group in Korean study while Japanese study had for 1-month only.

Despite these somewhat difference results, the overall message is the same. Patients may have similar outcomes when given clopidogrel (or other P2Y12 inhibitors) alone after an initial period of combined therapy with aspirin. This may be a particularly good news for those patients who are at higher risk of bleeding.

Anti-platelet Therapy after Cardiac Stent Placement

The type and duration of anti-platelet therapy after cardiac catheterization and stent placement (also called percutaneous coronary intervention or PCI) is an ongoing debate. Aspirin is under use for over 100 years and we know a lot about it. Plus, it is a cheaper drug. Clopidogrel, better known by its market name Plavix, is now in marker for many years and its generic versions are available. Almost all studies have examined the use of additional anti-platelet drugs after PCI on top of aspirin use. What if we examine the use of anti-platelet drugs on top of clopidogrel use?

A study published in JAMA examined this question in a multi-center, open-label, randomized clinical trial conducted in Japan. They enrolled 3045 patients to either 1 month of aspirin + clopidogrel therapy followed by clopidogrel therapy alone versus 12 months of aspirin + clopidogrel therapy. The outcome they were looking at was a combined outcome of cardiovascular death, myocardial infarction, stroke (ischemic or hemorrhagic), stent thrombosis, or bleeding.

I am certain that authors were hoping for finding that the two treatments were similar. To their surprise, not only 1-month of aspirin + clopidogrel followed by clopidogrel alone was similar in efficacy but was superior to the 12-months of aspirin + clopidogrel (2.35% vs. 3.70%; P<0.001). In other words, a shorter duration of combined therapy followed by clopidogrel therapy is as effective, if not better, than 12-months of combined therapy. These findings are important especially for patients who are at high risk of bleeding.

Abstain from Alcohol to Decrease Risk of Atrial Fibrillation

Here is a press release about a study that was presented by has not yet been published. Perhaps the best study design for evaluating the benefits/harms of alcohol.

Physicians Support Tighter FDA Control on New Drug Approval

An interesting research letter published in JAMA Internal Medicine reports that 80% of physicians agree with the strict FDA approval process to protect public from ineffective or dangerous drugs. Further, 60% thought that FDA should not allow off-label promotion of drugs to physicians.