Cancer associated ischemic stroke

In the 19^th century, French internist Armand Trousseau introduced for the first time the theory of hypercoagulable state in patients having malignancy, nowadays known as Trousseau’s syndrome (TS). TS is a systemic complication of malignancy which may manifest itself by thromboembolic events in the central nervous system. Approximately 40% of a general population develop a malignancy during their life span, and cancer as a co-diagnosis develops at certain timepoint in 1-2 of 10 stroke patients.¹ TS is mainly associated with “active cancer” diagnosed within 6-12 months prior or after the stroke event. This group of patients represents up to 5% of a general ischemic stroke population and up to 20% of patients with cryptogenic stroke.^2,3

Cancer associated ischemic stroke (CAIS) represents an increasing burden as the life expectancy lengthens and cancer therapy improves.⁴ Based on the available data, it is clear that CAIS requires a different approach to diagnostics, acute treatment and secondary prevention.⁵

The pathophysiology in CAIS is not completely clear and represents a complex spectrum of mechanisms related to the cancer itself, but also to its treatment with chemotherapeutics and radiotherapy. A hypercoagulable state caused by tumor pro-coagulants or adenocarcinoma released mucins as well as a non-bacterial thrombotic endocarditis may be involved in many of the cases.^6,7 These mechanisms lead to recurrent and usually therapeutically challenging microembolization.

The ischemic stroke may be the first clinical manifestation of occult cancer. Several clinical and diagnostic markers may help to unveil underlying malignancy. History of smoking, recent weight loss, occurrence of venous thromboembolism, upregulated coagulation activity in laboratory tests and multiple territory ischemic lesions on cerebral imaging are specific but lack sensitivity. An important question is when and who to screen for an occult cancer. A probability score consisting of the 3 variables D-Dimer, hemoglobin and history of smoking may guide the clinician in the decision making.⁸

Data on intravenous thrombolysis (IVT) in CAIS are scarce and mostly based on observation studies and sub-analysis of bigger IVT trials. Concerns about bleeding risk are in the front line. Caution and individual approach should be taken in patients with gastrointestinal tumors, CNS metastasis and intra-axial intracranial tumors.^2,9 There are also scarce data on endovascular treatment (EVT) since patients with concomitant cancer diagnosis have been excluded from randomized EVT trials. Similar rates of intracranial hemorrhage and recanalization in CAIS compared to non-cancer associated ischemic stroke have been showed in observational studies. However, platelet rich composition of thrombi and relatively more frequent tandem and multiple large vessel occlusions can make the EVT more challenging.¹⁰ The cancer related life expectancy must be considered in the acute therapeutic decision making and an individualized approach is required.

Patients with CAIS have often worse functional status prior to the stroke event, higher morbidity and higher stroke recurrence rate, all of which has a negative impact on the prognosis and further treatment.^5,11 The approach in secondary prevention is not scientifically established and may be challenging compared to the “traditional” ischemic stroke patients.¹² Injectable heparins are widely used for cancer related venous thromboembolism, mainly in the initial period, however high cost and inconvenience of a long-term administration are main drawbacks. Randomized control trials comparing direct oral anticoagulants (DOAC) and injectable heparins are needed to clarify eventual use of DOAC in this patient group.

CAIS represents an important field of stroke medicine but is quite unexplored. Further research in this field and establishing guidelines is an important task for following years.

1. White MC, Holman DM, Boehm JE, et al. Age and cancer risk: a potentially modifiable relationship. Am J Prev Med 2014; 46(3 Suppl. 1): S7–S15.
2. Selvik HA, Thomassen L, Bjerkreim AT, et al. Cancer-associated stroke: the Bergen NORSTROKE study. Cerebrovasc Dis Extra 2015; 5: 107–113.
3. Kim SJ, Park JH, Lee MJ, et al. Clues to occult cancer in patients with ischemic stroke. PLoS ONE 2012; 7: e44959.
4. Rioux B, Touma L, Nehme A, et al. Frequency and predictors of occult cancer in ischemic stroke: a systematic review and meta-analysis. Int J Stroke 2021; 16: 12–19.
5. Woock, M., Martinez-Majander, N., Seiffge, et al. (2022). Cancer and stroke: commonly encountered by clinicians, but little evidence to guide clinical approach. Therapeutic advances in neurological disorders, 15, 17562864221106362.
6. Dearborn JL, Urrutia VC and Zeiler SR. Stroke and cancer – a complicated relationship. J Neurol Transl Neurosci 2014; 2: 1039.
7. Navi BB, Singer S, Merkler AE, et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014; 83: 26–33.
8. Selvik HA, Bjerkreim AT, Thomassen L, et al. When to screen ischaemic stroke patients for cancer. Cerebrovasc Dis 2018; 45: 42–47.
9. Ladak AA, Sandhu S and Itrat A. Use of intravenous thrombolysis in acute ischemic stroke management in patients with active malignancies: a topical review. J Stroke Cerebrovasc Dis 2021; 30: 105728.
10. Jung S, Jung C, Hyoung Kim J, et al. Procedural and clinical outcomes of endovascular recanalization therapy in patients with cancer- related stroke. Interv Neuroradiol 2018; 24: 520–528.
11. Kneihsl M, Enzinger C, Wünsch G, et al. Poor short-term outcome in patients with ischaemic stroke and active cancer. J Neurol 2016; 263: 150–156.
12. Key, N. S., Khorana, A. A., Kuderer, N. M., et al. (2020). Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. Journal of Clinical Oncology, 38(5), 496-520.

Thrombectomy alone fails to show non-inferiority compared with thrombectomy plus intravenous alteplase – Full results of SWIFT DIRECT and DIRECT-SAFE published in The Lancet

Over the past years there has been a controversial debate over the additional value of intravenous thrombolysis prior to mechanical thrombectomy in patients with large vessel occlusion. Doubts about the effect of intravenous thrombolysis for large thrombi and concerns about potential risks, mainly the risk of intracerebral hemorrhage, have motivated a series of clinical trials comparing thrombectomy alone to thrombectomy plus intravenous thrombolysis.

Previous studies yielded controversial results. Two trials from China (DIRECT-MT and DEVT)^{1, 2} found direct thrombectomy to be non-inferior to thrombectomy plus intravenous thrombolysis. However, these trials have been criticized for different reasons including wide non-inferiority margins and organizational aspects as well as rather long door-to-needle time for alteplase. In contrast, two further trials from Europe (MR CLEAN-NO IV)³ and Japan (SKIP)⁴ did not show non-inferiority.

In the current issue of The Lancet two further trials on this research question have been published which will likely end the debate.

SWIFT DIRECT⁵ randomized 423 patients with stroke due to large vessel occlusion referred to 42 endovascular centers in Europe and Canada to either thrombectomy alone or intravenous thrombolysis plus thrombectomy. Primary outcome was a score of 2 or less on the modified Rankin scale at 90 days, and a non-inferiority margin of 12% was prespecified. Overall, rates of favorable outcome were high in both groups (57% in the thrombectomy alone group and 65% in the thrombectomy plus thrombolysis group). The adjusted risk difference was -7.3% with the lower limit of one-sided 95% CI of -15.1 crossing the predefined non-inferiority margin of -12%. Thus, thrombectomy alone was not shown to be non-inferior to thrombolysis plus thrombectomy. There were no differences in the frequency of symptomatic intracranial hemorrhage between the groups (2% vs. 3%) nor for any other safety endpoints. On the other hand, successful reperfusion was less common in the thrombectomy alone group.

The study is to be commended for the high quality of treatment in all participating centers reflected by short procedural times, high recanalization rates and an overall high percentage of patients achieving good functional outcome. In SWIFT DIRECT, rigorous inclusion and exclusion criteria ensured enrollment of a population most likely to benefit from thrombectomy alone. Nevertheless, point estimates favored combined treatment of intravenous alteplase plus thrombectomy. In patients below the age of 70, thrombectomy alone was even significantly less effective with lower odds of independent outcome at 90 days as compared to thrombectomy plus alteplase. SIWFT DIRECT also yield novel findings. The rates of postinterventional reperfusion where higher with combined treatment, which provides a likely explanation for the favorable outcome shifts observed in patients treated with alteplase plus thrombectomy.

The second trial, DIRECT-SAFE⁶ randomized 295 patients in 24 centers in Australia, New Zealand, China and Vietnam. The primary outcome was also an mRS score of 0-2 at 90 days, with a non-inferiority margin of -0.1. As in SWIFT DIRECT the trial did not show non-inferiority. Patients treated with thrombectomy alone had numerically lower rates of functional independence (55% vs. 61%) with a risk difference of -0.051 (95% CI -0.160 to 0.059). Safety outcomes were also comparable between the groups. In contrast to SWIFT DIRECT, DIRECT-SAFE also allowed for the use of Tenecteplase (17% of patients in the combined treatment group) and for enrollment of patients with M2 or basilar artery occlusion. Of note, almost half of the patients were enrolled in Asian regions, and in a region-based subgroup analysis Asian patients with combined treatment even showed significant better outcomes than those treated with thrombectomy alone. This makes it unlikely that the previous contrary results from the Chinese trials (DIRECT-MT and DEVT) are specific for Asian patients.

The main results of SWIFT DIRECT and DIRECT-SAFE are in line with those of MR CLEAN-NO IV and SKIP. Taken together, these four trials provide a clear answer to the question whether intravenous thrombolysis can be omitted prior to thrombectomy in patient with large vessel occlusion stroke. The answer is no, thrombolysis should not be omitted in these patients unless there are contraindications against intravenous thrombolysis.

References

1. Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med. 2020;382:1981-1993
2. Zi W, Qiu Z, Li F, Sang H, Wu D, Luo W, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke: The devt randomized clinical trial. JAMA. 2021;325:234-243
3. LeCouffe NE, Kappelhof M, Treurniet KM, Rinkel LA, Bruggeman AE, Berkhemer OA, et al. A randomized trial of intravenous alteplase before endovascular treatment for stroke. N Engl J Med. 2021;385:1833-1844
4. Suzuki K, Matsumaru Y, Takeuchi M, Morimoto M, Kanazawa R, Takayama Y, et al. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: The skip randomized clinical trial. JAMA. 2021;325:244-253
5. Fischer U, Kaesmacher J, Strbian D, Eker O, Cognard C, Plattner PS, et al. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial. The Lancet. 2022;400:104-15
6. Mitchell PJ, Yan B, Churilov L, Dowling RJ, Bush SJ, Bivard A, et al. Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4·5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial. The Lancet. 2022;400:116-25

Heart and brain: Is there a role for cardiac biomarkers in acute stroke treatment and prognosis?

Heart and brain are strongly connected with each other. Ischemic stroke is a well-known sequelae of cardiac diseases like atrial fibrillation (AF), heart failure, or myocardial infarction. At the same time, diseases of the heart may complicate treatment and outcome of acute stroke. In diagnosis and prognosis of cardiac disease, blood-based biomarkers play a pivotal role, and in the past years, there has been growing evidence indicating the clinical utility of cardiac biomarkers outside cardiac conditions. Increased levels of cardiac biomarkers are frequently observed in stroke patients, but their significance is still less clear.

On the one hand, the predictive value of markers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP) and cardiac toponins for risk of stroke in the general population has been investigated^1-3. On the other hand, by the time a stroke has occurred, cardiac troponins may help in identifying patients at risk for cardiovascular events. Cardiac troponins (troponin I, troponin T) are sensitive markers of acute coronary syndrome (ACS)⁴. Stroke and ACS largely share the same risk factors and thus may occur together. In line with this, current guidelines recommend measurement of troponin in acute stroke⁵. However, there are also other possible explanations for increased troponins in acute stroke, so that they may not exclusively indicate a treatment-relevant emergency calling for acute coronary intervention.

In a small pilot study including 29 patients with acute ischemic stroke (AIS) and increased levels of cardiac troponin who underwent coronary angiography, about 20-25% patients showed culprit lesions, i.e., coronary stenosis or local thrombus representing a target for coronary intervention. In contrast, nearly half of patients did not show any relevant coronary artery diseases⁶. Against this background the PRediction of acute coronary syndrome in acute ischemic StrokE (PRAISE) study has been started in 2018 to develop a diagnostic algorithm to better identify ACS as origin of cardiac troponin elevation in AIS patients. The primary hypothesis will test whether dynamic troponin levels (as compared to stable ones) indicate the presence of ACS. The study has enrolled the planned number of patients last year, and presentation of the results is expected at one of the large stroke meetings in the near future⁷.

Another possible application for cardiac biomarkers in stroke may be the identification of sources of cardiac embolism as cause of stroke, such as AF or severe heart failure. NT-proBNP is an established marker of hemodynamic stress, and increased levels of NT-proBNP are a diagnostic hallmark of heart failure⁸. Recently, MR-proANP has come into focus as a possible indicator of an increased risk of AF in patients with stroke⁹. The ongoing MidregiOnal Proatrial Natriuretic Peptide to Guide SEcondary Stroke Prevention (MOSES) study will address the question, whether stroke patients without AF but with increased levels of MR-proANP indicating atrial pathology may benefit from oral anticoagulation using non-Vitamin K antagonist oral anticoagulants (ClinicalTrials.gov Identifier: NCT03961334).

To summarize, cardiac biomarkers represent a promising diagnostic tool which may help in optimizing acute management and secondary prevention of stroke. Depending on the results of the aforementioned studies in the near future we may get used to measuring and interpreting cardiac biomarkers in the setting of acute stroke in our clinical practice.

References:

1. Di Castelnuovo A, Veronesi G, Costanzo S, Zeller T, Schnabel RB, de Curtis A, et al. Nt-probnp (n-terminal pro-b-type natriuretic peptide) and the risk of stroke. Stroke. 2019;50:610-617
2. Camen S, Palosaari T, Reinikainen J, Sprunker NA, Niiranen T, Gianfagna F, et al. Cardiac troponin i and incident stroke in european cohorts: Insights from the biomarcare project. Stroke. 2020;51:2770-2777
3. Berntsson J, Smith JG, Nilsson PM, Hedblad B, Melander O, Engstrom G. Pro-atrial natriuretic peptide and prediction of atrial fibrillation and stroke: The malmo preventive project. Eur J Prev Cardiol. 2017;24:788-795
4. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. Frisc study group. Fragmin during instability in coronary artery disease. N Engl J Med. 2000;343:1139-1147
5. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2018;49:e46-e110
6. Mochmann HC, Scheitz JF, Petzold GC, Haeusler KG, Audebert HJ, Laufs U, et al. Coronary angiographic findings in acute ischemic stroke patients with elevated cardiac troponin: The troponin elevation in acute ischemic stroke (trelas) study. Circulation. 2016;133:1264-1271
7. Nolte CH, von Rennenberg R, Litmeier S, Scheitz JF, Leistner DM, Blankenberg S, et al. Prediction of acute coronary syndrome in acute ischemic stroke (praise) – protocol of a prospective, multicenter trial with central reading and predefined endpoints. BMC Neurol. 2020;20:318
8. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-b-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med. 2005;352:666-675
9. De Marchis GM, Schneider J, Weck A, Fluri F, Fladt J, Foerch C, et al. Midregional proatrial natriuretic peptide improves risk stratification after ischemic stroke. Neurology. 2018;90:e455-e465