22-08-16 1 Sven O. Skouby, Professor,MD, DSc Director of Endocrinology and Reproductive Sciences Dep. Ob/Gyn. Herlev/Gentofte Hospital, Faculty of Health Sciences University of Copenhagen, 2 Department for Thrombosis Research, Institute of Public Health, University of Southern Denmark Combined hormonal contraceptionand VTE Learning objectives: Pathophysiology pharmacology, and epidemiological data Is there a difference between various brands? Definitions • Venous Thromboembolism (VTE) : • A condition in which a blood clot (thrombus) forms in a vein, most commonly in the deep veins of the legs or pelvis: • Deep Vein Thrombosis (DVT) • The thrombus can dislodge to the pulmonary arteries: • Pulmonary Embolism (PE) NICE 2012 VTE DVT Embolus in the blood circulation • DVT – Typically in the lower leg – Often asymptomatic or associated with minimal symptoms – Often undiagnosed • PE – Potentially life threatening • VTE is fatal in 1–2% of cases 1 ,2 VTE Clinical synthesis 1. Determine level of probability: Wells score 2. Confirm the clot: D-dimer test 3. Find the clot: imaging - DVT Doppler US:thigh - DVT Radio-opaquedyevenogram: calf - DVT MRI direct thrombusimaging: calf - PE Ventilation/perfusion scan - PE Helical CT pulmonary angiogram - PE MRI direct thrombus imaging DVT suspect ed: Wel l s scor e DVT l i kel y DVT unl i kel y D- di mer t est Posi ti ve Negati ve Proxi m l eg vei n US Posi ti ve Negati ve Proxi m l eg vei n US Posi ti ve Negati ve D- di mer t est Posi ti ve Negati ve Repeat US 6- 8 d Posi ti ve Negati ve DVT DVT No DVT No DVT No DVT No DVT DVT Deep Vein Thrombosis A dapted from: www.icsi.org 2012 www.nice.org.uk 2012
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SvenO.Skouby,Professor,MD, DSc
Director of Endocrinology and Reproductive SciencesDep. Ob/Gyn. Herlev/Gentofte Hospital, Faculty of Health SciencesUniversity of Copenhagen, 2Department forThrombosis Research,
Institute of Public Health, University of SouthernDenmark
CombinedhormonalcontraceptionandVTE
Learning objectives:
Pathophysiologypharmacology, andepidemiological data
Isthereadifferencebetweenvariousbrands?
Definitions• VenousThromboembolism(VTE) :• Acondition inwhich ablood clot (thrombus) forms inavein,most commonly inthedeep veins of thelegsorpelvis:
• Deep VeinThrombosis (DVT)
• The thrombus can dislodge tothe pulmonaryarteries:
• Pulmonary Embolism (PE)NICE 2012
VTE
DVT
Embolus in theblood circulation
• DVT– Typicallyinthelowerleg– Often asymptomaticorassociated withminimalsymptoms
– Often undiagnosed
• PE– Potentiallylifethreatening
• VTEisfatalin1–2%ofcases1,2
VTE Clinical synthesis
1.Determine levelof probability:Wells score2.Confirm the clot: D-dimer test3.Find the clot: imaging
• Prescribing practice• Healthy user effect (recency)
• Genetic Predisposition• Biological plausability
Danish Cohort Study: VTE Time Pattern vs. Progestagen Type
0
1
2
3
4
< 1 y 1 - 4 y > 4 y
Duration of Use [years]
RR
LNGDRSPCPADSGGSD
‘Early use effect’ seems to be influenced by year of market introduction in Denmark and market share over time. No ‘early use effect’ for LNG-containing OCs.
– Dose reduction from 30–40 to 20 µgEE: Further reduction of the ethinylestradiol dose to 20 µg EE appears tolead to an additional although onlyslight reduction in VTE risk [9, 57].
– Dose reduction from 30–40 µg EEto non-EE COC: Lidegaard et al.[57] note that progestogen-onlypreparations are not associated with ahigher risk of VTE for women of fer-tile age. Mini-Pills with levonor-gestrel or norethisterone: VTE rateratio of 0.59 (0.33–1.03) (data basedon 65,820 woman-years), or with75 µg desogestrel: VTE rate ratio of1.12 (0.36–3.49) (data based on 9,044woman-years). (Authors’ note: Clearindications are not available as towhether these results can be trans-ferred without qualification to womenwith marked risk factors.)
– Risk assessment of COC with estra-diol or estradiol valerate: Comparedto ethinyl estradiol, estradiol and es-tradiol valerate lead to less liver en-zyme induction and less impact onhemostasis. It is currently unclearwhether this theoretical advantagealso actually leads to a lower inci-dence of VTE.
Progestogens and their dosage: Theinfluence of different progestogens onthe risk of VTE is disputed. Levonor-gestrel is usually taken as the referencefor comparisons between differentprogestogens. According to the bestcurrently available studies [9], VTE in-cidence for levonorgestrel-containingCOCs with less than 50 µg EE lies atapproximately 8 VTE per 100,000woman-years. While it describes therisk for the typical OC user population,this value is of only limited use on ac-count of the strong age-dependency ofrisk in individual cases. See Figure 8for age-dependency of risk.
Incidence rates for norethisterone, nor-ethisterone acetate, and norgestimate aresimilar to that for levonorgestrel [57].
Studies published in the mid-1990sshowed a higher risk for gestoden anddesogestrel, which are known as third-generation progestogens, compared tolevonorgestrel (see meta-analysis byKemmeren et al. [120]. Studies that ad-just for the temporal dependence of risk(higher in the initial months of expo-sure following first use or resumption
of use) and correctly adjust quantita-tively for age differences showed nosignificant differences between the newand established progestogens of thetime. However, the methodologicalshortcomings of all available studies donot allow clear conclusions to be drawnregarding causal connections. Resultson cyproterone acetate (CPA) are alsoconflicting. This applies even to resultsfrom the same working group that ana-lyzed the same data source at differentpoints in time with different method-ologies. Thus Lidegaard [121] found anincidence of 31 VTE per 100,000woman-years with a confidence inter-val of 13–49 using a Danish patient reg-istry, whereas six years later [57] the
point estimate for incidence was clearlyoutside the 2003 confidence interval at71 VTE per 100,000 woman-years. Inthe same period of time the relative riskcompared to levonorgestrel rose from0.7–1.9. These differences cannot eas-ily be explained by coincidence, andhighlight the considerable method-ological difficulties in carrying out andevaluating studies of VTE risk in OCusers.
Regarding chlormadinone acetate(CMA), there are no indications of ahigher VTE risk compared to levonor-gestrel-containing COCs [122]. Thisalso applies to ethinyl estradiol-contain-ing COCs with dienogest [117].
Figure 7. Cigarette smoking as risk factor for VTE with use of OCs. Mod from [112].
Figure 8. BMI and age as risk factors for VTE with OC use. Weight and age are independent risk factors with ad-ditive effect. Mod from [112].
– Dose reduction from 30–40 to 20 µgEE: Further reduction of the ethinylestradiol dose to 20 µg EE appears tolead to an additional although onlyslight reduction in VTE risk [9, 57].
– Dose reduction from 30–40 µg EEto non-EE COC: Lidegaard et al.[57] note that progestogen-onlypreparations are not associated with ahigher risk of VTE for women of fer-tile age. Mini-Pills with levonor-gestrel or norethisterone: VTE rateratio of 0.59 (0.33–1.03) (data basedon 65,820 woman-years), or with75 µg desogestrel: VTE rate ratio of1.12 (0.36–3.49) (data based on 9,044woman-years). (Authors’ note: Clearindications are not available as towhether these results can be trans-ferred without qualification to womenwith marked risk factors.)
– Risk assessment of COC with estra-diol or estradiol valerate: Comparedto ethinyl estradiol, estradiol and es-tradiol valerate lead to less liver en-zyme induction and less impact onhemostasis. It is currently unclearwhether this theoretical advantagealso actually leads to a lower inci-dence of VTE.
Progestogens and their dosage: Theinfluence of different progestogens onthe risk of VTE is disputed. Levonor-gestrel is usually taken as the referencefor comparisons between differentprogestogens. According to the bestcurrently available studies [9], VTE in-cidence for levonorgestrel-containingCOCs with less than 50 µg EE lies atapproximately 8 VTE per 100,000woman-years. While it describes therisk for the typical OC user population,this value is of only limited use on ac-count of the strong age-dependency ofrisk in individual cases. See Figure 8for age-dependency of risk.
Incidence rates for norethisterone, nor-ethisterone acetate, and norgestimate aresimilar to that for levonorgestrel [57].
Studies published in the mid-1990sshowed a higher risk for gestoden anddesogestrel, which are known as third-generation progestogens, compared tolevonorgestrel (see meta-analysis byKemmeren et al. [120]. Studies that ad-just for the temporal dependence of risk(higher in the initial months of expo-sure following first use or resumption
of use) and correctly adjust quantita-tively for age differences showed nosignificant differences between the newand established progestogens of thetime. However, the methodologicalshortcomings of all available studies donot allow clear conclusions to be drawnregarding causal connections. Resultson cyproterone acetate (CPA) are alsoconflicting. This applies even to resultsfrom the same working group that ana-lyzed the same data source at differentpoints in time with different method-ologies. Thus Lidegaard [121] found anincidence of 31 VTE per 100,000woman-years with a confidence inter-val of 13–49 using a Danish patient reg-istry, whereas six years later [57] the
point estimate for incidence was clearlyoutside the 2003 confidence interval at71 VTE per 100,000 woman-years. Inthe same period of time the relative riskcompared to levonorgestrel rose from0.7–1.9. These differences cannot eas-ily be explained by coincidence, andhighlight the considerable method-ological difficulties in carrying out andevaluating studies of VTE risk in OCusers.
Regarding chlormadinone acetate(CMA), there are no indications of ahigher VTE risk compared to levonor-gestrel-containing COCs [122]. Thisalso applies to ethinyl estradiol-contain-ing COCs with dienogest [117].
Figure 7. Cigarette smoking as risk factor for VTE with use of OCs. Mod from [112].
Figure 8. BMI and age as risk factors for VTE with OC use. Weight and age are independent risk factors with ad-ditive effect. Mod from [112].
VT and drospirenoneVT Risk Rate rationo /10,000 DRSP/2nd
Dinger07 118 9.1 1.0 (0.6-1.8) 4th/2nd
Seeger07 57 13.0* 0.9 (0.5-1.6) 4th/?
Vlieg09 1,524 na 1.7 (0.7-3.9) 4th/2nd
Lidegaard09 4.213 7.8 1.6 (1.3-2.1) 4th/2nd
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Relative risk versus non-useConfirmed events only
Rate ratio
Lidegaard et al. BMJ 2011; 343: d6423 + new in press
Journal ofThrombosis and HaemostasisVolume 6 Issue 2 Page346-351, February2008
PATOPHYSIOLGY
Conclusions: This study observed thatthe differences inAPCresistance induced byOC containing different progestogenscan atleastin partbe explained by different effects of OC onfree protein Sand TFPI.
Oralcontraceptives (OC) containing different typesofprogestogens induce different sensitivities toactivatedprotein C (APC) measured with thethrombin generation-based APC-resistance test.These differences in APC resistancemay bethe biological explanation for the differences inthrombotic riskof the various pills. Themechanistic basis ofAPC resistance observed inOC users isunknown.
Although relative risk may appear alarming the absolute risk is small
Individual guidance minimizes thrombotic riskA balanced view on risks and benefits is mandatoryThe pill offers additional health benefitsIt has opened the door to modern contraception and
Conflicting results have also beenfound for drospirenone. Two large-scale prospective cohort studies(Fig. 11) [9, 123] and a German case-control study [117] showed no higherrisk, while two studies published in2009 – a retrospective cohort study inDenmark [57] and a Dutch case-controlstudy [113] – showed a slightly higherrisk compared to levonorgestrel-con-taining preparations. The two latterstudies, however, exhibit substantialmethodological shortcomings [124,125]. The Dutch study was not statisti-cally significant, and also not represen-tative for either the cases or controls. Inthe Danish study, short-term and long-term use were misclassified to a consid-erable degree, and information aboutimportant risk factors was not available.In addition, an independent validationstudy showed that probably around30% of the diagnoses that the authorstook from the Danish patient registrywere incorrect [126]. In addition,shortly before this statement went topress, the Boston Collaborative DrugSurveillance Program published the re-sults from two retrospective case-con-trol studies in the USA and England us-ing the PharMetrics [127] and GPRDdatabases [128]. Both studies yieldedhigher risk estimates for drospirenone-containing COCs with 30 µg EE. Thesestudies too show considerable short-comings. The GPRD results, which arebased on confirmed VTE, are not statis-tically significant. The incidence rates,which are too low overall, show that thedatabase compiled only some of theVTE (possible ‘ascertainment bias’). Inaddition, the substantially different riskestimates for pulmonary embolism anddeep venous thrombosis (factor 4) indi-cate the presence of considerable differ-ential diagnostic bias. The PharMetricsstudy was based on non-confirmedVTE from a database used for calculat-ing benefits, which cannot provide a re-liable scientific basis unless the diag-noses are confirmed by health records.The study was not able to reproduceknown risks such as the dependence onduration of use (see above), and did nothave access to information on majorprognostic factors.
In sum, the VTE risk of drospirenone-versus levonorgestrel-containing COCscannot be conclusively ascertained. Thestudies with the best methodology do not
Figure 9. VTE risk over time following start of COC use. Mod. from [114].
Figure 10. Influence of short breaks in Pill use on VTE risk. Mod. from [114].
Figure 11. VTE risk factors with OC use: VTE risk of drospirenone-containing OCs. Mod. from [9].
