Shifting Priorities in the Prevention of Venous Thromboembolism: Time to Focus on Overall Cardiovascular Health

In their study published in the present issue of the journal,[1] Liang et al analyzed the data of more than 275,000 individuals included in the UK Biobank, seeking to determine the association between a comprehensive index of cardiovascular health and the incidence of venous thromboembolism (VTE). Using the updated, structured Life's Essential 8 (LE8) score proposed by the American Heart Association,[2] the authors could show that individuals with a high level of cardiovascular health had an up to 41% lower risk of VTE over a median follow-up period of 12.6 years. This association was robust, remaining significant after adjustment for the patients' demographic characteristics, medical history and socioeconomic status, and it persisted regardless of genetic predisposition for VTE.[1]

The authors are to be congratulated on this relevant piece of work which elegantly highlights the shifting, or rather expanding, priorities of VTE prevention and care in the 21st century.

Case fatality[3] [4] and annual mortality rates[5] [6] associated with acute VTE have been declining in several countries since the beginning of the century; at the same time, hospitalizations for VTE, notably acute pulmonary embolism (PE), keep rising in ageing societies globally.[3] [7] The consequence of these opposing trends is that (1) an ever increasing number of individuals will be exposed to the risk of suffering VTE, and (2) a growing number of survivors of an index VTE episode will necessitate long-term care, aiming not only at the pharmacological secondary prevention of thrombosis and the management of possible complications of anticoagulant agents, but also at reducing the patients' overall thrombosis-related risk. Thus, primary and secondary VTE prophylaxis remains a high priority and its importance cannot be overemphasized.

The “classical” risk factors and predisposing conditions for deep vein thrombosis and PE are meanwhile well known, and their relative impact has been dissected and (partly) quantified.[8] [9] Guidelines have issued evidence-based recommendations regarding the use of anticoagulant agents for prophylaxis and treatment of VTE in various clinical settings.[10] [11] [12] [13] [14] [15] For example, an impressive body of evidence has accumulated in secondary VTE prophylaxis, showing that extended use of vitamin K antagonists (VKAs) and more recently direct oral anticoagulants (DOACs), at a therapeutic or reduced dose, is capable of minimizing the VTE recurrence risk.[16] [17] Importantly, DOACs further possess a superior safety profile related to major bleeding when compared to VKA,[17] [18] and this also appears to be the case for high-risk populations such as patients with VTE and cancer.[19] [20] Some caution is warranted in extrapolating these results to the general population with VTE as the studies leading to the approval of DOACs only enrolled patients with equipoise regarding the need for extended anticoagulant treatment.[16] Consequently, patients with strong persistent predisposing factors for thrombosis such as serious thrombophilia may have been underrepresented, and the efficacy (and safety) of DOACs thus overestimated in these studies.[18] Indeed, results from such trials may not be generalizable to older, multimorbid, and co-medicated patients.[21]

Notwithstanding, observational data from longitudinal studies appear to support the notion that, in the era of effective and safe oral anticoagulants, VTE recurrence or major bleeding is no longer the key determinants of the disease burden of thromboembolic disease over the long term.[22]

So, can we consider our mission accomplished, or is there something that we are still missing? The study by Liang et al[1] reminds us that effective thrombosis prevention demands much more than good anticoagulant drugs. In fact, it was only a few years ago that European guidelines on the management of VTE began to adopt a holistic approach and place emphasis on overall cardiovascular health and lifestyle modification.[9] The shifting focus of attention was combined with a call for dedicated outpatient care of patients at risk of thrombosis, including those having suffered prior VTE, with the help of behavioral frameworks and motivational interviewing to identify and modify associated risk factors.[9] Subsequent position papers further specified the goals of cardiovascular risk management,[23] and a recent systematic review and meta-analysis confirmed the involvement of typical cardiovascular risk factors in at least some clinical settings of VTE.[24] Even in this journal, many studies have examined the associations of VTE with lifestyle or environmental factors,[25] [26] [27] aside from other risks associated with cardiovascular diseases.[28] [29]

These and other[30] data, which may be explained by the link between arterial and venous thrombosis via inflammatory mechanisms underlying many cardiovascular diseases,[31] underline the urgent need for a holistic view and management of thrombotic disease ([Fig. 1]). But it is still a very long distance from here to the real world: the cardiovascular health indicators included in the LE8 score (diet, physical activity, [cessation of] nicotine exposure, sleep health, body mass index, blood lipids, and blood pressure)[2] are meanwhile universally acknowledged and appear quite “simple” to physicians and patients alike, yet for a large number of individuals at risk, they remain the hardest goal to reach, and early achievements are notoriously difficult to maintain over the long term.

Fig. 1 A broader look into the pathogenesis of venous thromboembolism.

How can we do better in the future and what should be our priorities? Contemporary medicine has thus far done what it can do best, namely successfully test the efficacy of new or established drugs in this indication. For example, a pooled analysis of two randomized controlled trials suggested that statin intake may reduce the risk of a first VTE event by 50% (hazard ratio: 0.53, 95% confidence interval: 0.37–0.75).[32] These results are strongly supported by a recent network meta-analysis showing a gradual increase in the summary effect of VTE reduction with increasing intensity of lipid-lowering treatment.[33] However, drugs alone cannot modify behavioral patterns and lifestyle, and simply giving some “good advice” to patients during routine ambulatory visits has extremely low chances of resulting in any sustainable benefits.

Structured outpatient rehabilitation programs[34] [35] appear more promising in this setting. Cardiopulmonary rehabilitation is a comprehensive intervention encompassing patient-tailored measures which start with exercise training and extend to patient education and overall lifestyle modification.[36] [37] [38] Strong evidence supports its prognostic benefits, including mortality reduction, but thus far it has mostly been derived from studies on heart failure, ischemic heart disease, and chronic obstructive pulmonary disease. To this date, there exist no major randomized trials on the effects of cardiopulmonary rehabilitation after PE. Promising findings were reported by two cohort studies which suggested that outpatient rehabilitation might improve physical and functional status and quality of life in patients with post-PE dyspnea,[35] [39] whereas a recent randomized trial showed better exercise capacity but mixed effects on quality of life in patients who underwent rehabilitation.[34] In view of persisting uncertainties as well as the medical and socio-economic relevance of the problem, solid evidence on the impact of structured cardiopulmonary rehabilitation programs on symptom alleviation and improvement in functional capacity and quality of life after PE is urgently needed. If proven successful, such interventions may help to reduce the burden imposed by VTE on individuals, health care systems, and the society.

Publication History

Received: 16 July 2024

Accepted: 16 July 2024

Article published online:
12 August 2024

• References

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