Diagnosis and Management of Cardiovascular Risk in Patients with Polycythemia Vera

Figures & data

Table 1 Cardiovascular Risk Factors in Polycythemia Vera

Risk Factor	Notes	Reference
Polycythemia vera-specific:
Clonal hematopoiesis	Epidemiological and experimental evidence supports the hypothesis that immune cell dysfunction mediated by clonal hematopoiesis is a risk factor for heart failure and CVD. Individuals with clonal hematopoiesis supported by the DNMT3A, TET2, ASXL1, or JAK2 (JAK2V617F) mutation are at increased risk of developing coronary heart disease after adjusting for classic CV risk factors.	[17,18]
Generic:
Smoking	Smoking facilitates the phenomenon of atherosclerosis and thrombotic phenomena. The risk of CV events doubles in smokers. In individuals under age 50, smoking increases the risk of CV events by 4–5 times. Passive smoking increases CV risk by 30%.	[19]
Blood pressure	Arterial hypertension is the main risk factor for ischemic heart disease, heart failure, cerebrovascular diseases, atrial fibrillation, and chronic renal failure.	[19]
Cholesterol	High levels of LDL-C produce atherosclerosis and are correlated with high CV risk.	[20]
Body weight	Being overweight and obesity are both associated with an increased risk of CVD because of hypertension, dyslipidemia, insulin resistance, systemic inflammation and prothrombotic status which increase the incidence of CVD and secondary events.	[21]
Diabetes mellitus	Diabetes mellitus is a major risk factor for CVD, while CVD is the major cause of death in patients with diabetes mellitus.	[22]
Diet	Alimentary habits impact CV risk and the risk of other chronic diseases such as cancer.	[21]
Physical activity	Sedentary (<0.5 h/week of physical activity) lifestyle is recognized as one of the major CV risk factors.	[21]

Abbreviations: ASXL1, ASXL transcriptional regulator 1; CV, cardiovascular; CVD, cardiovascular disease; DNMT3A, DNA methyltransferase 3 alpha; JAK2, Janus kinase 2; LDL-C, low-density lipoprotein cholesterol; TET2, tet methylcytosine dioxygenase 2.

Table 2 Cardiovascular Risk Determination Based on Anamnesis with Indications of Who Should Treat the patient²¹

Anamnesis	Yes?	Risk level	Treater
Past myocardial infarction	□	Very high risk	Referral to a specialist cardiology/hypertension center
Coronary or other arterial revascularization procedures	□
ACS and other arterial atherosclerotic occlusions	□
Past stroke or transient ischemic attack	□
Aorta aneurism	□
Peripheral artery disease	□
Diabetes mellitus:	□
● With organ damage (proteinuria)	□
● With other major risk factor:  ✓ uncontrolled grade 3 hypertension  ✓ severe dyslipidemia  ✓ smoking	□
Severe CKD (GFR<30 mL/min/1.73 m^2)	□
Age <50 years and SCORE2 ≥7.5%	□
Age 50–69 years and SCORE2 ≥10.0%	□
Age ≥70 years and SCORE2-OP ≥15.0%	□
Markedly elevated single risk factor: ● Uncontrolled grade 3 hypertension ● Severe dyslipidemia ● Smoking	□	High risk	Consider a referral to a specialist cardiology/hypertension center
Diabetes mellitus:	□
● Without organ damage (without proteinuria or neuropathy) ● Duration ≥10 years ● With additional risk factor	□
Moderate CKD (GFR 30–59 mL/min/1.73 m^2)	□
Age <50 years and SCORE2 2.5–7.49%	□
Age 50–69 years and SCORE2 5–9.99%	□
Age ≥70 years and SCORE2-OP 7.5–14.99%	□
TT echocardiogram:
Left ventricular hypertrophy (LVMi >95 g/m^2 [F] or ≥115 g/m^2 [M])	□
GLS > –18% or EF <52/54 M/F or altered kinetics	□
Resistant hypertension (not controlled by 3 drugs including a diuretic at full dose)	□
Diabetes mellitus:  Type 1 and age <35 years  Type 2 and age <50 years  Diabetes duration >10 years, without additional risk factors	□	Moderate risk	GP
Age <50 years and SCORE2 <2.5%	□	Low risk	GP
Age 50–69 years and SCORE2 <5.0%	□
Age ≥70 years and SCORE2-OP <7.5%	□

Notes: Very High Risk High Risk Moderate Risk Low Risk.

Abbreviations: ACS, acute coronary syndrome; CKD, chronic kidney disease; EF, ejection fraction; F, female; GFR, glomerular filtration rate; GLS, global longitudinal strain; GP, general practitioner; LVMi, left ventricular mass index; M, male; SCORE2, Systematic COronary Risk Evaluation 2; SCORE2-OP, Systematic COronary Risk Evaluation 2 in Older Persons; TT, transthoracic.

Table 3 Laboratory and Instrumental Examinations to Assess Cardiovascular Risk

First-line hemato-chemical examinations
Creatinine, Na and K
Creatinine clearance
Total cholesterol
HDL-C
Triglycerides
Glycemia
HbA1c (in patients with diabetes mellitus)
Albuminuria/creatininuria (to be carefully evaluated in patients with plasma cell dyscrasias)
Uricemia, iron levels
Instrumental examinations
Electrocardiogram
Echocardiogram with the assessment of systolic function and of the left ventricle mass
Home blood pressure monitoring ABPM in patients with arterial hypertension

Abbreviations: ABPM, ambulatory 24-hour blood pressure monitoring; HbA1c, glycated hemoglobin; HDL-C, high density lipoprotein cholesterol; K, potassium; Na, sodium.

Figure 1 Flow diagram for the diagnosis and management of the cardiovascular risk profile and prevention of thrombotic events in patients with PV.

Abbreviations: ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor antagonists; ASA, acetylsalicylic acid; BP, blood pressure; CCB, calcium channel blockers; CV, cardiovascular; Ht, hematocrit; LDL-C, low density lipoprotein cholesterol; PV, polycythemia vera.

Table 4 Therapeutic Goals for Modifiable Cardiovascular Risk Factors

Risk Factor	Target	Notes
Systolic blood pressure
18–65 years	130 mmHg	Standard target
>65 years	130–139 mmHg	If tolerated
Diastolic blood pressure	70–79 mmHg
LDL-C target^a
	<100 mg/dL	Patients with moderate CV risk or young patients with diabetes mellitus duration <10 years without other risk factors
	<70 mg/dL	Patients with high CV risk or diabetes mellitus without target organ damage
	<55 mg/dL	Patients with very high CV risk or diabetes mellitus with target organ damage or severe CKD or established atherosclerotic CVD
Triglycerides	<150 mg/dL
Fasting glycemia	<110 mg/dL
HbA1c	<6.5%

Notes: ^aIn patients with high and very high CV risk, at least a 50% reduction is required.

Abbreviations: CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol.

Figure 2 The algorithm for the sequential introduction of cholesterol lowering therapy.

Notes: Adapted with permission from Oxford University Press. Mach F, Baigent C, Catapano AL et al 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188. The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines, permission conveyed through Copyright Clearance Center, Inc.³⁸

Abbreviations: CV, cardiovascular; FH, familial hypercholesterolemia; LDL-C, low density lipoprotein cholesterol; N, no; PCSK9, proprotein convertase subtilisin/kexin type 9; Y, yes.

Table 5 Primary and Secondary Prevention of Thrombotic Events in Polycythemia Vera

Clinical Feature	Intervention
Primary prophylaxis
All PV patients	ASA
Unless
vWF activity <30%	Consider holding ASA
Platelet >1 million	Consider holding ASA
Ht ≥45%	Phlebotomy/cytoreduction to target Ht <45%
High-risk PV (age >60 years/past thrombosis)	Cytoreduction
Secondary prophylaxis
All patients	Cytoreduction
Typical VTE	Consider indefinite VKA for most patients, ASA if not on VKA
Atypical VTE	Indefinite VKA and DOAC
Arterial thrombosis	ASA

Notes: Adapted with permission from Springer Nature. Martin K. Risk factors for and management of MPN-associated bleeding and thrombosis. Curr Hematol Malig Rep. 2017;12(5):389–396.⁴⁴

Abbreviations: ASA, acetylsalicylic acid; DOAC, direct oral anticoagulant; Ht, hematocrit; PV, polycythemia vera; VKA, vitamin K antagonists; VTE, venous thromboembolism; vWf, von Willebrand factor.

Table 6 Antiplatelet Therapy in Patients with Acute Ischemic Heart Disease Who Had an ST-Elevation Myocardial Infarction, Non-ST-Elevation Myocardial Infarction or Aortocoronary Bypass

Clinical Situation	Intervention
All patients:	75–100 mg/day ASA (or 75 mg/day clopidogrel)
PCI to place a stent:	DAPT with 75–325 mg/day ASA + 75 mg/day clopidogrel (or prasugrel 10 mg/day if <75 years and >60 kg, or 90 mg BID ticagrelor) for 6 months if chronic coronary syndrome, 12 months if ACS (can be reduced if high bleeding risk case by case) single antiplatelet therapy thereafter
PCI to place a stent with atrial fibrillation or flutter:	Oral anticoagulation (VKA or DOAC) + DAPT (100 mg/day ASA + 75 mg/day clopidogrel) for up to 1 month depending on hemorrhagic risk. oral anticoagulation (DOAC/VKA) + single antiplatelet therapy (ASA or clopidogrel) until 1 year oral anticoagulation thereafter
PCI to place a stent and intraventricular thrombosis:	VKA for 6 months until complete resolution of the thrombosis. The duration of DAPT should be decided on a case-by-case basis

Abbreviations: ACS, acute coronary syndrome; ASA, acetylsalicylic acid; BID, twice daily; DAPT, double antiplatelet therapy; DOAC, direct oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonists.

Min KD, Kour A, Sano S, Walsh K. The role of clonal haematopoiesis in cardiovascular diseases: epidemiology and experimental studies. J Intern Med. 2020;288(5):507–517. doi:10.1111/joim.13130

 PubMed Web of Science ®Google Scholar

Yura Y, Sano S, Walsh K. Clonal hematopoiesis: a new step linking inflammation to heart failure. JACC Basic Transl Sci. 2020;5(2):196–207. doi:10.1016/j.jacbts.2019.08.006

 PubMedGoogle Scholar

Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380(9859):2224–2260. doi:10.1016/S0140-6736(12)61766-8

 PubMed Web of Science ®Google Scholar

Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459–2472. doi:10.1093/eurheartj/ehx144

 PubMed Web of Science ®Google Scholar

Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227–3337. doi:10.1093/eurheartj/ehab484

 PubMed Web of Science ®Google Scholar

Sarwar N, Gao P; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–2222. doi:10.1016/S0140-6736(10)60484-9

 PubMed Web of Science ®Google Scholar

Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188. doi:10.1093/eurheartj/ehz455

 PubMed Web of Science ®Google Scholar

Martin K. Risk factors for and management of MPN-associated bleeding and thrombosis. Curr Hematol Malig Rep. 2017;12(5):389–396. doi:10.1007/s11899-017-0400-3

 PubMed Web of Science ®Google Scholar