Anticoagulants

Aspirin and cancer treatment: systematic reviews and meta-analyses of evidence: for and against

Posted by

0


Abstract

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence ‘for’ and ‘against’ the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

Slider with three content items shown per slide. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide.

Abstract

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence ‘for’ and ‘against’ the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

Introduction

In 1965, Sir Austin Bradford Hill set nine criteria against which a causal relationship between a presumed cause and an observed effect could be assessed [1]. These criteria are still useful, but Hill’s comment on his eighth criterion: ‘Experiment’: ‘Occasionally it is possible to appeal to experimental evidence’ is somewhat dated. Now, thanks to Cochrane and others [2] the randomised controlled trial (RCT) is widely accepted as a ‘gold-standard’ within the hierarchy of evidence, and discussions about clinical interventions tend now to be dominated by whatever RCT evidence of clinical benefit is available. Randomised trials however have their own limitations and cannot give absolute certainty, so they therefore need to be considered in balance with other sources of evidence, including observational studies.

Hill’s criteria for a causal relationship also includes ‘Plausibility’ and in relation to aspirin and cancer, plausibility has been extensively established by the identification of effects of aspirin upon platelets and upon the many biological mechanisms relevant to cancer initiation, cancer metabolism, metastatic cancer spread, and thromboembolic complications in cancer [2].

In this review, we put together the published evidence from a wide range of sources which is favourable to the use of aspirin in cancer, and evidence that is unfavourable to its use. Finally, we urge the rights of patients with cancer to be sufficiently well informed about the risks and benefits of aspirin to enable them to raise the topic with members of their healthcare team, and to enable them, within discussion with their healthcare advisors, to decide whether or not to take the drug.

For aspirin use in cancer

Aspirin, biological mechanisms and clinical outcomes

The primary mechanism of aspirin is inhibition of the cyclooxygenase (COX) enzyme responsible for the formation of key signalling lipids known as prostanoids. While this is an important pathway in cancer signalling, recent evidence highlights additional targets for aspirin in tackling cancer progression directly, irrespective of COX activity [3, 4]. Such targets include energy metabolism involved in cancer proliferation, cancer associated inflammation [5] and platelet driven pro-carcinogenic activity [2].

Aspirin was also shown to affect DNA repair pathways, which is a mechanism of particular interest in colorectal cancers. Defects in DNA mismatch repair genes are responsible for hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome [6], as well as other types of colorectal cancer by causing the occurrence of instability of simple repeat sequences (termed ‘microsatellite instability’) [7, 8] Colon cancers which exhibit a high microsatellite instability are currently targeted by immunotherapy treatment to a good effect [8].

However, aspirin has also been shown to play a role in reducing the occurrence of these microsatellite instabilities in cancer cell lines independent of COX activity, supporting a direct role for aspirin in DNA repair pathways in cancer [7]. These findings were further supported by a recent study by Nonu et al. [9] which combined proteomics and Mendelian randomisation to demonstrate a beneficial effect of aspirin on colon cancer risk through an enhancement of DNA-repair mechanisms [2].

Beyond genetic repair, aspirin has also been shown to influence epigenetic mechanisms relating to inflammation-associated cancer progression. In many cancers, inflammation leads to the promotion of carcinogenesis via direct mutagenesis or activation of a cytokine response, leading to the formation of ‘tumour microenvironments’ which are characterised by the presence of immune cells, stromal cells and extracellular matrix which together serve to promote cancer progression [10, 11].

One way in which inflammation leads to this cancer promotion is through epigenetic changes, the heritable transcription alterations that do not include changes in DNA sequence [12]. Aspirin has been shown to interfere with these epigenetic cancer-related changes by mediating histone methylation, leading to an in vivo decrease of tumour growth and metastasis in animal models of metastatic cancer through interfering with cells in the tumour microenvironment [12, 13].

Together, these observations provide mechanistic evidence for the causal involvement of aspirin in modifying cancer pathways, DNA repair mechanisms as well as epigenetic mechanisms which jointly provide a ‘basic science’ basis to justify using aspirin as an adjunct to other pre-existing therapies (e.g., immunotherapy and cytotoxic chemotherapy) in the treatment of cancer progression and metastasis [2, 14].

Aspirin and vascular complications in cancer

Aspirin has been shown repeatedly to reduce thromboembolism, including in patients with cancer [15], and the biological mechanisms through which this is achieved have been well described [2].

In the UK records for 108,000 survivors of cancer were examined. Venous thromboembolism and other vascular causes of death were found to be substantially elevated in patients with almost all the cancers and were most pronounced in patients who had received chemotherapy [16].

In the USA the SEER programme on mortality in cancer patients reported that 11% of deaths amongst patients with twenty different cancers had been certified as due to vascular disease, most of which (76%) was heart disease [17]. This led the American Society of Clinical Oncology to recommend that prophylactic anticoagulants be considered for all hospitalised cancer patients [18]. Although aspirin use has to some extent been superseded by recently developed drugs for vascular protection, aspirin is still effective against thrombosis, including venous thrombosis [19].

Aspirin and metastatic cancer spread

The effect of aspirin on metastatic spread is of importance because metastases are responsible for much of the pain and the complications of cancer [20] and many of the deaths are attributable to metastases [21]. Platelets play a significant role in metastatic spread, and the relationship between these effects and the clinical outcomes has been detailed elsewhere [2, 22].

There appears to have been no systematic literature search and meta-analysis of clinical data on metastatic cancer, but many studies and overviews give evidence of substantial reductions by aspirin (ranging from about RR 0.48 (95% CI 0.30 to about 0.75), to RR 0.62 (0.52 and 0.75) [23, 24].

It is important to note that an effect on cancer spread indicates a value of aspirin that is independent of its effects upon cancer mortality [24,25,26]. Indeed any delay in the diagnosis and initiation of treatment would seem to make a reduction in metastatic spread of increased value.

Aspirin and cancer mortality

An effect of aspirin of particular interest is its enhancement of the mismatch repair of DNA [3], a protective mechanism against cancer within all of us. Failure of this mechanism leads to Lynch Syndrome, with a high risk of colon and other cancers and with an estimated prevalence of one in 279, or 0.35% in the general population [27].

Following the report of a reduction in mortality by aspirin in patients with this syndrome [28], the National Institute of Clinical Excellence in the UK judged the safety and effectiveness of aspirin favourable and recommends aspirin for the reduction of cancer in patients with the Syndrome [29].

A systematic literature search in 2016, together with two replicate searches in 2018 and in 2021 identified 118 published observational studies of cancer patients, representing about 1 million patients with 18 different cancers [30]. About a quarter of these patients reported taking aspirin at diagnosis (most usually for vascular protection, and therefore 75 or 81 mg daily) and a pooled analysis showed a reduction of 21% in all-cause mortality (HR 0.79; 95% CI 0.74, 0.86 in 56 reports that used hazard ratios and OR 0.57 (0.36, 0.89) in seven papers that reported odds ratios). Table 1 provides a summary of the key data.Table 1 Aspirin taking and mortality: meta-analysis of 118 published observational reports [30].

Full size table

Publication bias, arising from the selective publication of positive findings for an intervention such as aspirin, is a most important issue in meta-analyses such as the above. A ‘trim and fill’ testing procedure to restore symmetry in forest plots was therefore applied extensively to the data, and although the benefits of aspirin were reduced, significance of almost all the reductions remained [30].

In their report the authors identified 23 publications which had focused upon fifteen less studied cancers (naso- and oropharyngeal, oesophagus, gastrointestinal, gastric, rectal, liver, gallbladder, bladder, pancreas, bladder, endometrium, ovary, glioma, head and neck, lung, melanoma). Meta-analysis of these gave pooled reductions of around 30% in deaths associated with aspirin taking (HR 0.67; 0.60, 0.75 in 21 studies, and OR 0.47; 0.26, 0.83 in five studies) [30]. Together with the evidence of favourable effects of aspirin upon a wide range of biological mechanisms relevant to cancer mortality [3], these clinical outcomes suggest that aspirin is likely to be of benefit to patients within a very wide range of different cancers.

Unfortunately, in contrast to observational studies, very few randomised trials of aspirin and mortality have been reported. The pooled results of four early trials based upon a total of 722 patients with cancer gave a suggestive pooled reduction associated with aspirin of about 9% in cancer deaths [30]. Currently, a number of randomised trials which test aspirin and mortality are in progress. These focus upon the common cancers: colon, breast, prostate and one in lung cancer. One of these trials, based upon 3021 selected patients in remission from a HER2-negative breast cancer, has already reported [31]. This trial was ended prematurely because aspirin was associated with a possible increase of about 25% in deaths.

The opportunity to conduct long-term follow-up studies of deaths in subjects who had already participated in randomised trials of aspirin and vascular disease was taken by Rothwell and colleagues in Oxford. Subjects who had been involved in up to 51 randomised vascular trials were followed-up for up to 20 years. Consistently, a reduction in cancer deaths was shown in these studies: (OR 0.58; 95% CI 0.44, 0.78 in an overview of six vascular trials [23], and OR 0.84; 0.75, 0.94) in an overview of 51 randomised vascular trials) [32].

An opportunistic trial was conducted in a subset of subjects who were participants in a randomised trial of prophylactic aspirin. During the study 502 subjects developed cancer of the prostate, and follow-up of these showed a 30% relative reduction attributable to aspirin (HR 0.68, 95% CI 0.52, 0.90 in cancer deaths and HR 0.72; 0.61, 0.9 in all-cause deaths) [33], and the evidence given by aspirin taken by patients with the Lynch syndrome [27], together with Mendelian randomisation studies, powerfully supplement the evidence available from conventional randomised trials.

Aspirin and the duration of survival

A few authors report estimates of the length of additional survival associated with aspirin taking by patients with cancer. A number of different summary statistics of survival have been used, and these defy pooling, but the additional survivals range from about 3 months up to 3 years [30].

Using a different approach, a group in Liverpool extracted extensive baseline data, including aspirin taking, from the records for 44,000 patients with colon cancer. With these they constructed a formula giving predicted estimates of survival [34]. Entering into the formula the details for a typical non-diabetic patient aged 70 with colon cancer, the inclusion of aspirin increases the estimate of survival by about 5 years for a man, and about 4 years for a woman.

Against aspirin use in cancer

Additional gastrointestinal bleeding

A bleed, either gastrointestinal or intra-cerebral, is a crisis for a patient and especially for patients who are already seriously ill [35,36,37]. Yet the seriousness of bleeds attributable to aspirin, and not just their frequency, should be evaluated against the benefits attributable to the use of aspirin [38]. The most serious bleeds are those that are responsible for death, and survival/death is a clear dichotomy, requiring no value judgement.

In a systematic literature search eleven randomised trials which included data on fatal bleeding were identified [39]. These 11 RCTs included together a total of 121,094 subjects, followed for an average of 2.8 years, as shown in Table 2.Table 2 GI bleeding in a meta-analysis of data from 11 RCTs [39] (average duration 2.8 years).

Full size table

These data confirm the usual excess risk of all ‘major’ bleeds for aspirin (RR 1.55), equivalent to about one per bleed per 1000 persons per year. Note however that the 50% increase above the background risk of bleeding from a peptic ulcer, stomach infection or other pathology, means that amongst patients who are taking aspirin the risk of a GI bleed being truly attributable to aspirin is only one in every three bleeds.

However, the proportion of ‘major’ bleeds in subjects who had been randomised to aspirin that led to death was 4% in those who had been randomised to aspirin while 8% of bleeds in subjects randomised to placebo were fatal. Clearly, this implies that overall, the bleeds truly attributable to aspirin must be of a much lower severity than other bleeds attributable to stomach pathology. This is further confirmed by the absence of any increased risk of a fatal bleed associated with aspirin taking, as shown in the third cell in the above table (RR 0.77), and this final conclusion has been confirmed in overviews of bleeding reported by other authors [39].

It is unfortunate however that the scientific literature on the issue of aspirin and bleeding appears to have been swamped by a host of statements about serious dangers of aspirin, most unsupported by any evidence while some are total misinterpretations. Probably the most misleading and most influential item on the web was a report issued by Reuters on the 14th June 2017, stating: ‘daily aspirin causes 3000 deaths from bleeding in Britain every year’ [40]. This claim was taken up and very widely and repeatedly publicised in the web and the media across the world. The report by Reuters was however a totally invalid, having been based on a prospective study of 3166 older patients, all of whom (93–97%) were taking aspirin. There were therefore no control subjects and no valid estimate of the independent contribution of aspirin to the fatal bleeds can be made.

In addition to this, there have been reports of so-called ‘neurogenic’ bleeding in patients with acute ischaemic strokes. A report from six thousand patients in the Fukuoka Stroke Registry describes 89 patients (1.4%) who experienced a GI bleed within a week of admission for acute ischaemic stroke [41]. O’Donnell et al. reported an incidence rate of 1.5% within a week of admission for acute ischaemic stroke, associated with a high rate of death [42] and Davenport et al. estimated an incidence of 3% [43]. In the study which led to the Reuters claim of 3000 deaths 2000 (65%) of the patients had had a stroke!

Additional cerebral bleeding

Unlike a gastrointestinal bleed, the consequences of a cerebral bleed, whether or not fatal, can be of a severity comparable to a cancer or a myocardial infarct in a risk/benefit evaluation. Estimates of additional risk in patients on aspirin are around one or two events per ten thousand (10,000) subject-years [35, 44, 45]. The major factor in cerebral bleeding however is hypertension [46], and in an RCT of aspirin based on more than 18,000 hypertensive patients—all of whom were receiving ‘optimal’ antihypertensive treatment—there were no additional cerebral bleeds in patients randomised to aspirin [47].

Inadequate support from randomised trials of aspirin

At present, the strength of the case for the use of aspirin in cancer lies in the wealth of evidence of benefit in observational cohort and case-control studies of aspirin taken by patients with cancer, while support from RCTs is seriously limited to a small number of trials, and there are serious inconsistencies between these.

There are calls by many for a delay on the promotion of aspirin until there is better and more consistent evidence from randomised trials. However, one seriously questions how much evidence, from how many randomised trials, in how many different cancers, will be required to resolve the uncertainties in the pooled observational studies.

Discussion

The first ethical principle in clinical practice is: do no harm: non-maleficence. In the evaluation of excess bleeding attributable to aspirin, the absence of any valid evidence of fatal bleeding (see Table 2 and the related references) is reassuring and indicates that evaluated against cancer, or a thrombotic vascular event, aspirin is a reasonably safe drug. This conclusion is supported by the recommendation of aspirin by NICE as a treatment for some patients at risk of cancer [29].

Beneficence—perhaps the second most important ethical principle of relevance to clinical interventions—has been established with difference levels of probability for the three main clinical effects of aspirin. A reduction in thromboembolic events has been widely and repeatedly established with a high level of certainty, and a reduction in metastatic cancer spread seems to be a reasonable expectation based upon both clinical reports and the effect of aspirin upon relevant biological mechanisms. While the evidence for a reduction in mortality lacks consistent support from RCTs, both the evidence of benefit in Lynch syndrome [12], and further evidence from Mendelian randomisation studies [2] give considerable support.

Furthermore, the effect of aspirin on both the biological mechanisms relevant to thromboembolism and to metastatic cancer spread, are different to the biological mechanisms of aspirin and cancer growth and survival. This seems to indicate that aspirin is a useful cancer treatment whether or not the drug does truly affect survival.

However, the wealth of favourable evidence on aspirin and mortality in observational cohort and case-control studies of patients with cancer cannot be lightly dismissed. Granted, confounding by unknown factors independent from aspirin is possible and perhaps even likely, yet the evidence from Mendelian randomisations studies powerfully supplements the few results from randomised trials.

The situation with cancer in the poorer countries is clearly ethically unjust. One in every six deaths worldwide is due to cancer [48], giving an estimated 9.6 million deaths in 2018, with around 70% of the deaths in low- and middle income- countries [49]. WHO points out that most cancers in the poorer countries are diagnosed at a very late stage, when most treatments are no longer effective—even if treatments were available, which they are not in many countries [50]. Against that background the promotion of aspirin would be of enormous benefit in developing countries.

The ethical issue of autonomy concerns the right of a patient to be involved in every aspect of his or her care and treatment [51, 52]. Aspirin is inexpensive and readily available globally. It is easily taken with none of the highly distressing effects that accompany some of the cancer therapies. While aspirin should best be considered as a possible adjunct treatment for cancer, yet for those patients who refuse the more aggressive treatments, and for patients for whom palliative care is judged to be appropriate, aspirin should be considered.

Given the relative safety of aspirin; given its likely reduction in metastatic cancer spread; given its associated reduction in thromboembolic complications and given the support by NICE for aspirin use in a subset of cancers, is it ethically reasonable for patients to be kept in ignorance about the probable risk/benefit balance of aspirin?

Early in this work, in 2010, a challenge was published in the BMJ: “The debate about aspirin has consumed the medical profession for over 30 years, [now, almost 50 years!] yet almost no public participation or consultation has occurred” [53]. In response, a 3-day far ranging enquiry—a ‘Citizens’ Jury—under the general title: ‘My Health—whose responsibility?’ was held in Cardiff with members of the general public who had no vested interest in the topic [54]. Over several days, the jury listened to a range of (sometimes contradictory) expert evidence, and the evidence of ‘experts by experience’, and vigorously debated amongst themselves the various issues raised. An immediate outcome of this initiative was a verdict by the sixteen members of the ‘jury’ that patients and the public should be directly involved in the evaluation of the outcomes of research, and in the assessment of its relevance to clinical practice and to public health policy…. and to this last the jurors unanimously added the phrase: ‘even before there is agreement between doctors’ [54].

In the UK, the NHS Ethical Clinical Guidelines establish that people have a right to be involved in discussion and have a right to make informed decisions about their care [55]. However the law in the UK goes further and in a ‘Landmark Decision’ given by the UK supreme court in 2015 it was stated: ‘If information is material, doctors should generally disclose it. They should not wait for the patient to ask’ [56]. Surely evidence on the possible benefits of aspirin are highly ‘material’ to patients with cancer and to their carers!

‘Medicine is a science of uncertainty and an art of probability.’

Sir William Osler (1849-1919)

Frequently described as the father of Modern Medicine. (1849-1919)

Conclusions

A major strength of the case for the promotion of aspirin as a treatment of cancer lies in the consistent evidence of a reduction in the thromboembolic complications of cancer and in the consistent evidence of a reduction in metastatic cancer spread. The main weakness, however, lies in the lack of support of a reduction in deaths from trials with random allocation of aspirin. However, the suggestive evidence from observational studies, together with evidence from Mendelian randomisation powerfully favour the use of low-dose aspirin.

Finally: aspirin is inexpensive, readily available and has none of the highly aggressive side effects of some of the cancer treatments. It would therefore seem to be only fair and reasonable that knowledge of the true risk and probable benefits of the drug should be widely publicised amongst cancer patients and their carers—so that, as one oncologist has predicted:

There could be benefit ‘…both to the affluent and the indigent within developed and under-developed countries’… and…’a truly global impact on cancer mortality could be realised

Direct Thrombin Inhibitor Shows Benefit for Progressing Stroke

Posted by

0


Urgent anticoagulation with argatroban shows no bleeding downside in EASE trial

A computer rendering of a blood clot.

Argatroban could revive the practice of acute anticoagulation for reducing disability after stroke, based on the EASE trial from China.

In patients with acute ischemic stroke and early neurological deterioration, urgent application of the direct thrombin inhibitor increased a person’s likelihood of a good functional outcome (modified Rankin Scale score 0-3) at 90 days compared with usual care (80.5% vs 73.3%; RR 1.10, 95% CI 1.01-1.20).

This would appear to counter the evidence accumulated over the years showing that parenteral anticoagulation, typically IV heparin, has not been as beneficial in acute progressing stroke as believed decades ago.

Importantly, argatroban’s efficacy did not come at the cost of excess bleeding, with rates of symptomatic intracranial hemorrhage (SICH) comparable between groups (0.9% vs 0.7%, P=0.78), reported Min Lou, MD, PhD, of the Second Affiliated Hospital, Zhejiang University School of Medicine in Hangzhou, and colleagues in JAMA Neurologyopens in a new tab or window.

“No harmful profile of argatroban was observed even in patients who received intravenous alteplase, suggesting the possible safety of anticoagulants,” the EASE investigators wrote.

The trial selected progressing stroke patients who had an increase of 2 or more points on the NIH Stroke Scaleopens in a new tab or window within 48 hours from symptom onset. Participants were randomized 1:1 within 48 hours to standard therapy with or without argatroban. The argatroban group received IV argatroban at a continuous infusion of 60 mg per day for 2 days, followed by 20 mg per day for 5 days, whereas controls received standard therapy such as antiplatelets.

The relatively low dose of argatroban in EASE “may explain the low rates of bleeding observed,” suggested Brett Cucchiara, MD, of the University of Pennsylvania in Philadelphia, and Jennifer Majersik, MD, of University of Utah in Salt Lake City, in an accompanying editorialopens in a new tab or window.

The pair cited the higher dose of argatroban tested in the ARAISopens in a new tab or window trial, in which the agent failed to better neurologic function over alteplase alone and was associated with excess SICH to boot.

“Many questions remain” and “these new data will undoubtedly fan the flames of the age-old controversy over if and when patients with acute stroke should be treated with parenteral anticoagulation,” according to Cucchiara and Majersik.

“Combining antiplatelet therapy with low-dose anticoagulation has demonstrated efficacy for reducing vascular events, particularly stroke, in patients with chronic atherosclerotic disease. Given the EASE trial results, should this same strategy be tested more extensively in acute stroke?” they posed. “If low-dose acute anticoagulation combined with antiplatelet therapy is effective in patients with early deterioration, would it be even more effective if targeted at patients at high risk of deterioration before they worsen?”

Lou and colleagues also noted that the ideal timing of anticoagulation therapy after early neurological deterioration remains to be determined in future studies. Results also need to be confirmed in non-Chinese populations.

EASE was an open-label trial conducted in 28 Chinese sites. The 628 stroke patients averaged age 65 and 63.7% were men.

Study authors acknowledged that 98% of the argatroban group underwent the complete procedure of argatroban at a median 24 hours from symptom onset to randomization, whereas among controls, 89.8% were treated appropriately according to study protocol.

Nevertheless, per-protocol results were similar to those from the full analysis, Lou’s group maintained.

The authors reported that while the control group was more likely to get dual antiplatelet therapy, this did not change the primary outcome. “Even with more application of dual antiplatelet therapy, the control group had less good functional outcome than the argatroban group, which may indicate the potential effect of argatroban.”

“However, our study was neither powered nor specifically targeted at this treatment effect,

Window for Post-Stroke Antiplatelet Therapy Can Be Extended

Posted by

0


Combined clopidogrel and aspirin initiated within 72 hours of a stroke is associated with a lower risk for a new stroke at 90 days but has a higher risk for moderate to severe bleeding than aspirin alone, new results of a randomized trial showed, suggesting treatment can be given past the current 24-hour time window for the use of dual antiplatelet therapy in patients with an ischemic stroke.

METHODOLOGY:

  • The analysis, part of the Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, included 6100 patients, median age 65 years and 35.8% women, with a mild ischemic stroke, defined as a National Institutes of Health Stroke Scale (NIHSS) score ≤ 5, or a high-risk transient ischemic attack of presumed atherosclerotic origin, from 222 sites in China.
  • Researchers randomly assigned patients within 72 hours of symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2-90) plus aspirin (100-300 mg on day 1 and 100 mg daily on days 2-21) or clopidogrel placebo plus aspirin (100-300 mg on day 1 and 100 mg daily for days 2-90) in a 2 × 2 factorial design that also compared immediate vs delayed statin therapy.
  • The primary efficacy outcome was any new stroke (ischemic or hemorrhagic) within 90 days.
  • Secondary efficacy outcomes included a composite of cardiovascular events (stroke, myocardial infarction, or death from cardiovascular causes) within 90 days.
  • The primary safety outcome was moderate to severe bleeding as defined according to criteria from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial.

TAKEAWAY:

  • A new stroke within 90 days occurred in 7.3% in the clopidogrel-aspirin group and 9.2% in the aspirin group (hazard ratio [HR], 0.79; 95% CI, 0.66-0.94; P = .008).
  • A composite cardiovascular event occurred in 7.5% in the clopidogrel-aspirin group and 9.3% in the aspirin group (HR, 0.80; 95% CI, 0.67-0.96).
  • Moderate to severe bleeding occurred in 0.9% in the clopidogrel-aspirin group and in 0.4% in the aspirin group (HR, 2.08; 95% CI, 1.07-4.04; P = .03), and risk for any bleeding was 3.1% in the clopidogrel-aspirin group and 2.1% in the aspirin group (HR, 1.50; 95% CI, 1.09-2.06).
  • Adverse events occurred in 21.3% in both groups, and serious adverse events occurred in 3.5% in the combination group and 2.9% in the aspirin group.

IN PRACTICE:

“The results of our trial potentially broaden the time window for the initiation of treatment, although there was more bleeding with the dual regimen than with the monotherapy,” the authors wrote.

In an accompanying editorial, Anthony S. Kim, MD, Weill Institute for Neurosciences, University of California, San Francisco, said he welcomes evidence to support expanding the time window for dual antiplatelet therapy, adding: “Perhaps new, more targeted antithrombotic agents on the horizon may hold promise for delivering an even more favorable balance of benefits and risks among patients with stroke.”

SOURCE:

The study was conducted by Ying Gao, MD, Department of Neurology, Beijing Tiantan Hospital, Beijing, China, and colleagues. It was published online on December 28, 2023 in The New England Journal of Medicine. Results from the INSPIRES trial were also reported at the European Stroke Organisation Conference in May.

LIMITATIONS:

The study excluded important patient populations such as those with a stroke of presumed cardioembolic origin and with moderate or severe stroke (NIHSS score > 5) and those who had undergone thrombolysis or thrombectomy. More than 98% of enrolled patients were Han Chinese who had a relatively high rate of intracranial artery stenosis, which may have contributed to the benefit from dual antiplatelet therapy. The results may not be generalized to White and Black patients with a stroke.

Short Aspirin Therapy Noninferior to DAPT for 1 Year After PCI for ACS

Posted by

0


Stopping aspirin within 1 month of implanting a drug-eluting stent (DES) for acute coronary syndrome (ACS) followed by ticagrelor monotherapy was shown to be noninferior to 12 months of dual antiplatelet therapy (DAPT) in net adverse cardiovascular and bleeding events in the T-PASS trial.

“Less than one month of DAPT followed by ticagrelor monotherapy met a noninferiority threshold and provided evidence of superiority to 12 months of ticagrelor-based DAPT for a 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily due to a significant reduction in bleeding events,” senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Seoul, Korea, told attendees here at the Transcatheter Cardiovascular Therapeutics 2023 congress.

“This study provides evidence that stopping aspirin within 1 month after implantation of drug-eluting stents for ticagrelor monotherapy is a reasonable alternative to 12-month DAPT as for adverse cardiovascular and bleeding events,” Hong concluded.

The study was published in Circulation ahead of print to coincide with the presentation.

Three Months to 1 Month

Previous trials (TICO and TWILIGHT) have shown that ticagrelor monotherapy after 3 months of DAPT can be safe and effectively prevent ischemic events after percutaneous coronary intervention (PCI) in ACS or high-risk PCI patients.

The current study aimed to investigate whether ticagrelor monotherapy after less than 1 month of DAPT was noninferior to 12 months of ticagrelor-based DAPT for preventing adverse cardiovascular and bleeding events in patients with ACS undergoing PCI with a DES implant.

T-PASS, carried out at 24 centers in Korea, enrolled ACS patients aged 19 years or older who received an ultrathin, bioresorbable polymer sirolimus-eluting stent (Orsiro, Biotronik). They were randomized 1:1 to ticagrelor monotherapy after < 1 month of DAPT (n = 1426) or to ticagrelor-based DAPT for 12 months (n = 1424).

The primary outcome measure was net adverse clinical events (NACE) at 12 months, consisting of major bleeding plus major adverse cardiovascular events. All patients were included in the intention-to-treat analysis.

The study could enroll patients aged 19 to 80 years. It excluded anyone with active bleeding, at increased risk for bleeding, with anemia (hemoglobin ≤ 8 g/dL), platelets < 100,000/μL, need for oral anticoagulation therapy, current or potential pregnancy, or a life expectancy less than 1 year.

Baseline characteristics of the two groups were well balanced. The extended monotherapy and DAPT arms had an average age of 61 ± 10 years, were 84% and 83% male and had diabetes mellitus in 30% and 29%, respectively, with 74% of each group admitted via the emergency room. ST-elevation myocardial infarction occurred in 40% and 41% of patients in each group, respectively.

Results showed that stopping aspirin early was noninferior and possibly superior to 12 months of DAPT.

For the 12-month clinical outcome, fewer patients in the < 1-month DAPT followed by ticagrelor monotherapy arm reached the primary clinical endpoint of NACE vs the ticagrelor-based 12-month DAPT arm, both in terms of noninferiority (P < .001) and superiority (P = .002). Similar results were found for the 1-month landmark analyses.

T-PASS: Primary Outcome

Endpoint< 1-Month DAPT Followed by Ticagrelor Monotherapy (Cumulative Incidence, %)Ticagrelor-Based 12-Month DAPT (Cumulative Incidence, %)Hazard Ratio (95% Confidence Interval)P (Noninferiority)P (Superiority)
12-month clinical outcome2.85.20.54 (0.37 – 0.80)< .001.002
1-month landmark analyses2.04.10.48 (0.31 – 0.75)< .001.001

For both the 12-month clinical outcome and the 1-month landmark analyses, the curves for the two arms began to diverge at about 150 days, with the one for ticagrelor monotherapy essentially flattening out just after that and the one for the 12-month DAPT therapy continuing to rise out to the 1-year point.

In the < 1-month DAPT arm, aspirin was stopped at a median of 16 days. Panelist Adnan Kastrati, MD, Deutsches Herzzentrum München, Technische Universität, Munich, Germany, asked Hong about the criteria for the point at which aspirin was stopped in the < 1-month arm.

Hong replied, “Actually, we recommend less than one month, so therefore in some patients, it was the operator’s decision,” depending on risk factors for stopping or continuing aspirin. He said that in some patients it may be reasonable to stop aspirin even in 7 to 10 days. Fewer than 10% of patients in the < 1-month arm continued on aspirin past 30 days, but a few continued on it to the 1-year point.

There was no difference between the < 1-month DAPT followed by ticagrelor monotherapy arm and the 12-month DAPT arm in terms of major adverse cardiac and cerebrovascular events at 1 year (1.8% vs 2.2%, respectively; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.50 – 1.41; log-rank, P = .51).

However, the 12-month DAPT arm showed a significantly greater incidence of major bleeding at 1 year: 3.4% vs 1.2% for < 1-month aspirin arm (HR, 0.35; 95% CI, 0.20 – 0.61; log-rank, P < .001).

Hong said that a limitation of the study was that it was open-label and not placebo-controlled. However, an independent clinical event adjudication committee assessed all clinical outcomes.

Lead discussant Marco Valgimigli, MD, PhD, Cardiocentro Ticino Foundation, Lugano, Switzerland, noted that T-PASS is the fifth study to investigate ticagrelor monotherapy versus a DAPT, giving randomized data on almost 22,000 patients.

“T-PASS showed very consistently with the prior four studies that by dropping aspirin and continuation with ticagrelor therapy compared with the standard DAPT regimen is associated with no penalty…and in fact leading to a very significant and clinically very convincing risk reduction, and I would like to underline major bleeding risk reduction,” he said, pointing out that this study comes from the same research group that carried out the TICO trial.

Long-term Clopidogrel Has Advantages After Coronary Stenting

Posted by

0


At 5 years, clopidogrel was noninferior to aspirin for net adverse clinical events in patients who have undergone percutaneous coronary intervention (PCI) using drug-eluting stents but was superior to aspirin in reducing secondary endpoints of myocardial infarction (MI) and ischemic stroke, a new analysis showed.

METHODOLOGY:

  • One-year results from the randomized, multicenter Short and Optimal Duration of Dual Antiplatelet Therapy 2 (STOPDAPT-2) trial showed clopidogrel monotherapy after a month of dual antiplatelet therapy (DAPT) substantially reduced major bleeding compared with continued DAPT using clopidogrel and aspirin, without an increase in cardiovascular events, among Japanese patients undergoing PCI.
  • According to the trial protocol, clopidogrel monotherapy was continued in the 1-month DAPT group (clopidogrel group), while the 12-month DAPT group was shifted to aspirin monotherapy (aspirin group). The authors reported 5-year results in 3005 patients — mean age 68.6 years, 22.3% women, and 38.3% with acute coronary syndrome at baseline.
  • The primary endpoint was net adverse clinical events, defined as a composite of cardiovascular outcomes (death from cardiovascular causes, MI, stent thrombosis, stroke) and major or minor bleeding.
  • Secondary outcomes included the separate cardiovascular and bleeding components of the primary endpoint and newly diagnosed cancer because there’s some suggestion aspirin might protect against colorectal cancer.

TAKEAWAY:

  • The clopidogrel group was noninferior, but not superior, to the aspirin group for the primary endpoint (11.75% vs 13.57%; hazard ratio [HR], 0.85; 95% CI, 0.70-1.05; P for noninferiority < .001; P for superiority = .13).
  • The clopidogrel group was superior to the aspirin group for the major secondary cardiovascular endpoint (8.61% vs 11.05%; HR, 0.77; 95% CI, 0.61-0.97; P for noninferiority < .001; P for superiority = .03), mainly driven by reduction in MI and ischemic stroke.
  • The cumulative 5-year incidence of major secondary bleeding was not lower in the clopidogrel group (4.44% vs 4.92%; HR, 0.89; 95% CI, 0.64-1.25; P = .51), possibly due to the high prevalence of proton pump inhibitor use (79%), said the authors, nor was the incidence of newly diagnosed cancer.

IN PRACTICE:

“Clopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI,” the authors wrote.

“This important study confirms that ischemic protection post-PCI is better ensured by clopidogrel than aspirin from 1 month to 5 years,” wrote Anne Bellemain-Appaix, MD, Cardiology Department, Antibes Hospital, Antibes, and Sorbonne University, Paris, France, and a colleague in an accompanying editorial, adding that beyond 1 month, DAPT de-escalation to a P2Y12 inhibitor alone “may become the new standard of care among select, if not most, patients.”

SOURCE:

The study was carried out by Hirotoshi Watanabe, MD, Department of Cardiology, Hirakata Kohsai Hospital, Hirakata, Japan, and colleagues. It was published online on January 2, 2023, in the Journal of the American College of Cardiology.

LIMITATIONS:

Although overall adherence to antiplatelet therapy was more than 80% during follow-up, participants with clinical events such as revascularization often changed antiplatelet therapy, so they may not have been treated as allocated. The study enrolled only Japanese patients, and there might be risk differences in cardiovascular and bleeding events across ethnicities. Researchers didn’t have data on the status of medications other than antithrombotic therapy. The study didn’t include a formal cost-effectiveness analysis, which would be crucial for adopting a lifelong treatment (aspirin is relatively inexpensive).

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

Posted by

0


Abstract

BACKGROUND

Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied.

METHODS

In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding — both assessed within 90 days.

RESULTS

A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel–aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P=0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel–aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P=0.03).

CONCLUSIONS

Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel–aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding.

Clopidogrel vs Aspirin Monotherapy Beyond 1 Year After Percutaneous Coronary Intervention

Posted by

0


Abstract

Background

It remains unclear whether clopidogrel is better suited than aspirin as the long-term antiplatelet monotherapy following dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI).

Objectives

This study compared clopidogrel monotherapy following 1 month of DAPT (clopidogrel group) with aspirin monotherapy following 12 months of DAPT (aspirin group) after PCI for 5 years.

Methods

STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy 2) is a multicenter, open-label, adjudicator-blinded, randomized clinical trial conducted in Japan. Patients who underwent PCI with cobalt-chromium everolimus-eluting stents were randomized in a 1-to-1 fashion either to clopidogrel or aspirin groups. The primary endpoint was a composite of cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) or major bleeding (TIMI major or minor bleeding).

Results

Among 3,005 study patients (age: 68.6 ± 10.7 years; women: 22.3%; acute coronary syndrome: 38.3%), 2,934 patients (97.6%) completed the 5-year follow-up (adherence to the study drugs at 395 days: 84.7% and 75.9%). The clopidogrel group compared with the aspirin group was noninferior but not superior for the primary endpoint (11.75% and 13.57%, respectively; HR: 0.85; 95% CI: 0.70-1.05; Pnoninferiority < 0.001; Psuperiority = 0.13), whereas it was superior for the cardiovascular outcomes (8.61% and 11.05%, respectively; HR: 0.77; 95% CI: 0.61-0.97; P = 0.03) and not superior for major bleeding (4.44% and 4.92%, respectively; HR: 0.89; 95% CI: 0.64-1.25; P = 0.51). By the 1-year landmark analysis, clopidogrel was numerically, but not significantly, superior to aspirin for cardiovascular events (6.79% and 8.68%, respectively; HR: 0.77; 95% CI: 0.59-1.01; P = 0.06) without difference in major bleeding (3.99% and 3.32%, respectively; HR: 1.23; 95% CI: 0.84-1.81; P = 0.31).

Conclusions

Clopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI.

Antiplatelet agents and anticoagulants for hypertension

Posted by

0


BACKGROUND: The main complications of elevated systemic blood pressure (BP), coronary heart disease, ischaemic stroke, and peripheral vascular disease, are related to thrombosis rather than haemorrhage. Therefore, it is important to investigate if antithrombotic therapy may be useful in preventing thrombosis-related complications in patients with elevated BP.

OBJECTIVES: To conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with elevated BP, including elevations in systolic or diastolic BP alone or together. To assess the effects of antiplatelet agents on total deaths or major thrombotic events or both in these patients versus placebo or other active treatment. To assess the effects of oral anticoagulants on total deaths or major thromboembolic events or both in these patients versus placebo or other active treatment.

SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials (RCTs) up to January 2021: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 12), Ovid MEDLINE (from 1946), and Ovid Embase (from 1974). The World Health Organization International Clinical Trials Registry Platform and the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) were searched for ongoing trials.  SELECTION CRITERIA: RCTs in patients with elevated BP were included if they were = 3 months in duration and compared antithrombotic therapy with control or other active treatment.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data for inclusion criteria, our prespecified outcomes, and sources of bias. They assessed the risks and benefits of antiplatelet agents and anticoagulants by calculating odds ratios (OR), accompanied by the 95% confidence intervals (CI). They assessed risks of bias and applied GRADE criteria.  MAIN RESULTS: Six trials (61,015 patients) met the inclusion criteria and were included in this review. Four trials were primary prevention (41,695 patients; HOT, JPAD, JPPP, and TPT), and two secondary prevention (19,320 patients, CAPRIE and Huynh). Four trials (HOT, JPAD, JPPP, and TPT) were placebo-controlled and two studies (CAPRIE and Huynh) included active comparators. Four studies compared acetylsalicylic acid (ASA) versus placebo and found no evidence of a difference for all-cause mortality (OR 0.97, 95% CI 0.87 to 1.08; 3 studies, 35,794 participants; low-certainty evidence). We found no evidence of a difference for cardiovascular mortality (OR 0.98, 95% CI 0.82 to 1.17; 3 studies, 35,794 participants; low-certainty evidence). ASA reduced the risk of all non-fatal cardiovascular events (OR 0.63, 95% CI 0.45 to 0.87; 1 study (missing data in 3 studies), 2540 participants; low-certainty evidence) and the risk of all cardiovascular events (OR 0.86, 95% CI 0.77 to 0.96; 3 studies, 35,794 participants; low-certainty evidence). ASA increased the risk of major bleeding events (OR 1.77, 95% CI 1.34 to 2.32; 2 studies, 21,330 participants; high-certainty evidence). One study (CAPRIE; ASA versus clopidogrel) included patients diagnosed with hypertension (mean age 62.5 years, 72% males, 95% Caucasians, mean follow-up: 1.91 years). It showed no evidence of a difference for all-cause mortality (OR 1.02, 95% CI 0.91 to 1.15; 1 study, 19,143 participants; high-certainty evidence) and for cardiovascular mortality (OR 1.08, 95% CI 0.94 to 1.26; 1 study, 19,143 participants; high-certainty evidence). ASA probably reduced the risk of non-fatal cardiovascular events (OR 1.10, 95% CI 1.00 to 1.22; 1 study, 19,143 participants; high-certainty evidence) and the risk of all cardiovascular events (OR 1.08, 95% CI 1.00 to 1.17; 1 study, 19,143 participants; high-certainty evidence) when compared to clopidogrel. Clopidogrel increased the risk of major bleeding events when compared to ASA (OR 1.35, 95% CI 1.14 to 1.61; 1 study, 19,143 participants; high-certainty evidence). In one study (Huynh; ASA verus warfarin) patients with unstable angina or non-ST-segment elevation myocardial infarction, with prior coronary artery bypass grafting (CABG) were included (mean age 68 years, 79.8% males, mean follow-up: 1.1 year). There was no evidence of a difference for all-cause mortality (OR 0.98, 95% CI 0.06 to 16.12; 1 study, 91 participants; low-certainty evidence). Cardiovascular mortality, non-fatal cardiovascular events, and all cardiovascular events were not available. There was no evidence of a difference for major bleeding events (OR 0.13, 95% CI 0.01 to 2.60; 1 study, 91 participants; low-certainty evidence).  AUTHORS’ CONCLUSIONS: There is no evidence that antiplatelet therapy modifies mortality in patients with elevated BP for primary prevention. ASA reduced the risk of cardiovascular events and increased the risk of major bleeding events.  Antiplatelet therapy with ASA probably reduces the risk of non-fatal and all cardiovascular events when compared to clopidogrel. Clopidogrel increases the risk of major bleeding events compared to ASA in patients with elevated BP for secondary prevention.  There is no evidence that warfarin modifies mortality in patients with elevated BP for secondary prevention.  The benefits and harms of the newer drugs glycoprotein IIb/IIIa inhibitors, clopidogrel, prasugrel, ticagrelor, and non-vitamin K antagonist oral anticoagulants for patients with high BP have not been studied in clinical trials. Further RCTs of antithrombotic therapy including newer agents and complete documentation of all benefits and harms are required in patients with elevated BP.

Do Anticoagulants Preserve Function and Quality of Life in Older Adults with Atrial Fibrillation?

Posted by

0


The Problem,

An 82-year-old woman with hypertension and diabetes is seen in the clinic for newly diagnosed atrial fibrillation (AF). She uses a walker and fell twice last year. She completes activities of daily living (ADLs) independently. Should she be prescribed an anticoagulant?

AF markedly increases the risk of ischemic stroke, which often results in disability and threatens independence.1 Anticoagulants reduce stroke rates but simultaneously increase hemorrhage rates. Unfortunately, predictors of benefit and harm overlap considerably; for example, advanced age predicts both stroke and hemorrhage risk. Guidelines give clear-cut therapeutic recommendations based on stroke risk but provide less specific guidance on balancing the increased hemorrhage risk.2 Although risk models help quantify bleeding risk, the consequences of bleeding (e.g., disability) in older adults are ill defined. The result is a quagmire.

The Pros and Cons of Anticoagulant Use in Older Adults with AF

Randomized controlled trials (RCTs) unequivocally demonstrate that anticoagulants reduce stroke rates, including in older adults.3 We have long understood that anticoagulants also increase the risk of intracranial hemorrhage, which is uncommon but devastating. By comparison, many consider the more common extracranial hemorrhage (e.g., gastrointestinal hemorrhage) to be a temporary inconvenience. While this is likely true for younger adults, bleeding may be more consequential for older adults.

Stroke prevention is important because strokes often result in a sudden loss of ADL independence. Now consider that hospitalization for any reason poses a risk to older adults’ independence: one in three develop lasting hospital-acquired disability.4 Even when the underlying disease is treated, hospitalization of older adults may result in lost ADL independence. Given the typical management for hemorrhage (e.g., procedures, not allowing patients to eat), such admissions are bound to result in hospital-acquired disability. Although stroke-associated disability has been reported in RCTs, hemorrhage-associated disability has not been commonly reported.

Older also adults prize quality of life.5 Anticoagulants impose costs to quality of life not captured in RCTs, including so-called nuisance bleeding, delays for urgent procedures, physician visits, medication interactions, and out-of-pocket expenses. Such costs are particularly burdensome to vulnerable older adults. They are hardly a niche population: 80% of older adults with AF are vulnerable with one or more geriatric syndromes (e.g., falls, frailty).6

What We Know

Guidelines recommend using the CHA2DS2-VASc score to estimate stroke risk and offer anticoagulants above a certain threshold — one that nearly all older adults with AF surpass.2,6 The recommendation implies that above the threshold, the benefits outweigh the risks; however, this threshold has not yet been tested with regard to disability and quality of life.

Faced with uncertainty, anticoagulant use in older adults with AF is far below what the guidelines suggest: only 45% consistently use anticoagulants.7 When surveyed about the decision not to treat specific patients in their care, physicians cite frailty, falls, and life expectancy — geriatric features that are under-addressed in RCTs.8,9

The ELDER-AF trial addressed anticoagulant use in older adults with AF.10 The investigators randomly assigned adults 80 years of age or older who were not considered candidates for therapeutic anticoagulation to placebo or low-dose edoxaban, a direct-acting oral anticoagulant. The trial again demonstrated that anticoagulants reduce stroke risk by 66%.

The trial also underscored the trouble with anticoagulants in older adults. Major bleeding, the primary safety outcome, was not statistically higher with treatment. However, this outcome excludes clinically relevant nonmajor bleeding, which is common and consequential.11 Clinically relevant nonmajor bleeding includes hemorrhages requiring interventions like hospitalization, endoscopy, and surgery. Using this more germane end point, anticoagulation increased bleeding risk by 65%. In a trial in which one sixth of all participants had major or clinically relevant nonmajor bleeding, no data were presented on the outcomes of bleeding events. We are left wondering — did bleeding result in lost independence or decrements in quality of life?

What We Need

A trial that compares oral anticoagulants to placebo for older adults with AF where function and quality of life are the primary outcomes would capture the broader impact of therapy that many older adults prioritize. Such a trial would answer straightforward questions: If the 82-year-old woman described at the beginning of this article uses an anticoagulant, will it improve her chances of remaining ADL independent? Will it sustain her quality of life?

The work ahead is to co-design and execute a trial with stakeholders — older adults with AF, caregivers, and physicians — whose decisions we seek to inform. This trial would recruit a population similar to the ELDER-AF trial: older adults with AF for whom physicians have misgivings about anticoagulants or patients who, for any reason, decided not to use anticoagulants despite their physician’s recommendation. Based on projections from disability rates after stroke and hemorrhage, and studies of quality of life in AF,12,13 this trial would need to randomly assign approximately 1600 patients to treatment with 18 months of follow-up to detect a 5% absolute change in ADL independence and a 0.15-SD change in the 36-Item Short Form Health Survey physical component score. The results of such a trial could provide clarity for millions of older adults with AF and their physicians who, with current data, struggle to balance the benefits and harms of anticoagulants.

New ACG, CAG guidelines for antithrombotic therapy in acute GI bleeding, periendoscopy

Posted by

0


The ACG and Canadian Association of Gastroenterology have developed recommendations for the management of anticoagulants and antiplatelets during acute gastrointestinal bleeding and the elective periendoscopic period.

“We aimed to bring together clinical content and methodological experts in gastrointestinal endoscopy and GI bleeding, hematology, and cardiology to create pragmatic, principle-based guidance related to managing antiplatelet and anticoagulant drugs before endoscopy and in the setting of gastrointestinal bleeding,” Neena S. Abraham, MD, MSc (Epi), FACG, of the Mayo Clinic in Scottsdale, Arizona, told Healio. “In this important update, we critically evaluated the published literature related to temporary interruption and resumption of these agents and the use of reversal agents. Clinicians can have confidence in our recommendations based on the unprecedented rigor used in evaluating the literature and the multidisciplinary perspective addressing common clinical scenarios.”

HGI0322Abraham_Graphic_01
ACG and CAG developed guidelines for management of anticoagulants and antiplatelets  during acute GI bleeding and periendoscopy. Source:

Guidelines for the management of antithrombotic agents in the setting of acute GI bleed include:

  • Fresh frozen plasma (FFP) administration should not be used in patients on warfarin who are either hospitalized or under observation with acute GI bleeding.
  • Prothrombin complex concentrate (PCC) administration is neither recommended nor not recommended.
  • PCC administration is recommended in patients on warfarin who are hospitalized or under observation for a GI bleed, compared with FFP administration.
  • Vitamin K is not recommended in these patients.
  • Idarucizumab should not be administered in patients on dabigatran.
  • Andexanet alfa should not be administered in patients on rivaroxaban or apixaban.
  • PCCs should not be administered in patients on direct oral anticoagulants (DOACs).
  • Platelet transfusions are not recommended in patients on antiplatelet agents.
  • In patients with GI bleeding on cardiac acetylsalicylic acid (ASA) for secondary prevention, ASA should not be held; however, in patients whose ASA was held, ASA should be resumed on the day hemostasis is endoscopically confirmed.

Guidelines for the management of antithrombotic agents in the elective endoscopic setting include:

  • Warfarin should be continued rather than temporarily interrupted.
  • In patients who held warfarin in the periendoscopic period, bridging anticoagulation is not recommended.
  • DOACs should temporarily be interrupted rather than continued.
  • P2Y12 receptor inhibitor should be temporarily interrupted while continuing ASA in patients on dual antiplatelet therapy for secondary prevention.
  • ASA should not be interrupted in patients on ASA 81–325 mg/d for secondary prevention.