Skip to main content
SpringerLink
Log in

Cardiovascular Events Associated With Different Combined Oral Contraceptives

A Review Of Current Data

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Studies of combined oral contraceptive (COC) use and cardiovascular disease have been conducted against a background of low cardiovascular risk in young women, changing COC composition and changing user selection and monitoring. Studies of myocardial infarction have found inconsistent results, possibly because of differences in the prevalence of risk factors (particularly smoking and raised blood pressure) in the populations studied. In the absence of a history of smoking and other conventional risk factors, current users of modern COCs probably do not have an increased risk of myocardial infarction. Neither are former users at risk. Evidence for important differences in the risk of myocardial infarction between formulations is weak and contradictory.

Current users of low estrogen dose COCs have a small increased risk of ischaemic stroke although most of the risk occurs in women with other risk factors (notably smoking, hypertension and probably a history of migraine). Former users of COCs do not have an increased risk of ischaemic stroke. There is insufficient information to determine whether major differences in the risk of ischaemic stroke exist between products. Current users appear to have a modestly elevated risk of haemorrhagic stroke, mainly in women older than 35 years; former users do not. Data examining the risk of haemorrhagic stroke in current COC users with other risk factors are very sparse, as are those relating to the haemorrhagic stroke risk associated with particular COCs.

Numerous studies have found, with remarkable consistency, an elevated risk of venous thromboembolism among current users of low estrogen dose COCs. The risk is substantially elevated among women with various inherited clotting factor defects. The effects in COC users with other risk factors for venous thrombosis tend to be less pronounced and more inconsistent. A number of studies have found higher relative risks among current users of low estrogen dose COCs containing desogestrel or gestodene, than among users of similar products containing levonorgestrel. A number of explanations, in terms of bias or confounding, have been proposed for these clinically small differences. At best, empirical evidence for these explanations, is weak.

The risk of cardiovascular disease of any description is low in COC users. Women can minimise, and possibly eliminate entirely, their arterial risks by not smoking and by having their blood pressure checked before using a COC (in order to avoid its use if raised blood pressure is discovered). Users may decrease their venous thromboembolic risk by their choice of COC preparation although the effects will be modest.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II

Similar content being viewed by others

References

  1. Jordan WM. Pulmonary embolism. Lancet 1961; II: 1146–7

    Article  Google Scholar 

  2. Hannaford PC, Owen-Smith V. Using epidemiological data to guide clinical practice: review of studies on cardiovascular disease and use of combined oral contraceptives. BMJ 1998; 316: 984–7

    Article  PubMed  CAS  Google Scholar 

  3. World Health Organization Scientific Group on Cardiovascular Disease and Steroid Hormone Contraception. Cardiovascular disease and steroid hormone contraception: report of a World Health Organization scientific group. World Health Organization technical report series: 877. Geneva, Switzerland: World Health Organization, 1998

  4. Meirik O. Cardiovascular safety and combined oral contraceptives. Contraception 1998; 57: 135–6

    Article  PubMed  CAS  Google Scholar 

  5. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet 1997; 349: 1202–9

    Google Scholar 

  6. Lewis MA, Heinemann LAJ, Spitzer WO, et al. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women: results for the transnational study on oral contraceptives and the health of young women. Contraception 1997; 56: 129–40

    Article  PubMed  CAS  Google Scholar 

  7. Mant J, Painter R, Vessey M. Risk of myocardial infarction, angina and stroke in users of oral contraceptives: an updated analysis of a cohort study. Br J Obstet Gynaecol 1998; 105: 890–6

    Article  PubMed  CAS  Google Scholar 

  8. Sidney S, Petitti DB, Queensberry Jr CP, et al. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 1996; 88: 939–44

    Article  PubMed  CAS  Google Scholar 

  9. Sidney S, Siscovick DS, Petitti DB, et al. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation 1998; 98: 1058–63

    Article  PubMed  CAS  Google Scholar 

  10. Dunn N, Thorogood M, Faragher B, et al. Oral contraceptives and myocardial infarction: results of the MICA case-control study. BMJ 1999; 318: 1579–84

    Article  PubMed  CAS  Google Scholar 

  11. Petitti DB, Sidney S, Queensberry CP. Oral contraceptive use and myocardial infarction. Contraception 1998; 57: 143–55

    Article  PubMed  CAS  Google Scholar 

  12. Rosenberg L, Kaufman DW, Helmrich SP, et al. Myocardial infarction and cigarette smoking in women younger than 50 years of age. J Am Med Assoc 1985; 253: 2965–9

    Article  CAS  Google Scholar 

  13. Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study. BMJ 1989; 298: 165–8

    Article  PubMed  CAS  Google Scholar 

  14. Jick H, Jick S, Myers MW, et al. Risk of acute myocardial infarction and low-dose combined oral contraceptives. Lancet 1996; 347: 627–8

    Article  PubMed  CAS  Google Scholar 

  15. Thorogood M. Stroke and steroid hormonal contraception. Contraception 1998; 57: 157–67

    Article  PubMed  CAS  Google Scholar 

  16. Lidegaard Ø. Oral contraception and risk of cerebral thromboembolic attack: results of a case-control study. BMJ 1993; 306: 956–63

    Article  PubMed  CAS  Google Scholar 

  17. Schwartz SM, Petitti DB, Siscovick DS, et al. Stroke and use of low-dose oral contraceptives in young women: a pooled analysis of two US studies. Stroke 1998; 29: 2277–84

    Article  PubMed  CAS  Google Scholar 

  18. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996; 348: 498–505

    Google Scholar 

  19. Carolei A, Marini C, De Matteis G. History of migraine and risk of cerebral ischaemia in young adults. Lancet 1996; 347: 1503–6

    PubMed  CAS  Google Scholar 

  20. Oleckno WA. The risk ofstroke in young adults: an analysis of the contribution of cigarette smoking and alcohol consumption. Public Health 1988; 102: 45–55

    Article  PubMed  CAS  Google Scholar 

  21. Heinemann LA, Lewis MA, Spitzer WO, et al. Thromboembolic stroke in young women. A European case-control study on oral contraceptives. Contraception 1998; 57: 29–37

    Article  PubMed  CAS  Google Scholar 

  22. Heinemann LAJ, Lewis MA, Thorogood M, et al. Oral contraceptives and risk of thromboembolic stroke. BMJ 1997; 315: 1502–4

    Article  PubMed  CAS  Google Scholar 

  23. Tzourio C, Tchindrazanarivelo A, Iglesias S, et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 1995; 310: 830–3

    Article  PubMed  CAS  Google Scholar 

  24. Chang CL, Douglas M, Poulter N, et al. Migraine and stroke in young women: case-control study. BMJ 1999; 318: 13–8

    Article  PubMed  CAS  Google Scholar 

  25. Lidegaard Ø, Kreiner S. Cerebral thrombosis and oral contraceptives. Contraception 1998; 57: 303–14

    Article  PubMed  CAS  Google Scholar 

  26. Poulter NR, Chang CL, Farley TMM, et al. Effect on stroke of different progestogens in low estrogen dose oral contraceptives. Lancet 1999; 354: 301–2

    Article  PubMed  CAS  Google Scholar 

  27. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results from an international, multicentre, case-control study. Lancet 1996; 348: 505–10

    Google Scholar 

  28. Jick SS, Myers MW, Jick H. Risk of idiopathic cerebral haemorrhage in women on oral contraceptives with differing progestogen components. Lancet 1999; 354: 302–3

    Article  PubMed  CAS  Google Scholar 

  29. Realini JP, Encarnacion CE, Chintapalli KN, et al. Oral contraceptives and venous thromboembolism: a case-control study designed to minimize detection bias. J Am Family Pract 1997; 10: 315–21

    CAS  Google Scholar 

  30. Bloemenkamp KWM, Rosendaal FR, Büller HR, et al. Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med 1999; 159; 65–70

    Article  PubMed  CAS  Google Scholar 

  31. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995; 346: 1575–82

    Google Scholar 

  32. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589–93

    Article  PubMed  CAS  Google Scholar 

  33. Suissa S, Blais L, Spitzer WO, et al. First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1997; 56: 141–6

    Article  PubMed  CAS  Google Scholar 

  34. Lidegaard Ø, Edström B, Kreiner S. Oral contraceptives and venous thromboembolism. Contraception 1998; 57: 291–301

    Article  PubMed  CAS  Google Scholar 

  35. Herings RMC, Urquhart J, Leufkens HGM. Venous thromboembolism among new users of different oral contraceptives. Lancet 1999; 354: 127–8 [Published erratum apprears in Lancet 1999; 354: 1478]

    Article  PubMed  CAS  Google Scholar 

  36. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, et al. Venous thromboembolism and oral contraceptives [letter]. Lancet 1999; 354: 1469

    Article  PubMed  CAS  Google Scholar 

  37. Pabinger I, Kyrle PA, Heistinger M, et al. Thrombosis risk of women with hereditary antithrombin III, protein C- and protein S- deficiency taking oral contraception medication. Thromb Haemost 1994; 71; 458–552

    Google Scholar 

  38. Vandenbroucke JP, Koster T, Briet E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453–7

    Article  PubMed  CAS  Google Scholar 

  39. Andersen BS, Olsen J, Neilsen GL, et al. Third generation oral contraceptives and heritable thrombophilia as risk factors of non-fatal venous thrombolism. Thromb Haemost 1998; 79: 28–31

    PubMed  CAS  Google Scholar 

  40. Martinelli I, Taioli E, Bucciarelli P, et al. Interaction between G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999; 19: 700–3

    Article  PubMed  CAS  Google Scholar 

  41. Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793–7

    Article  PubMed  CAS  Google Scholar 

  42. De Bruijn SFTM, Stam J, Koopman MMW, et al. Case-control study of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions. BMJ 1998; 316: 589–92

    Article  PubMed  Google Scholar 

  43. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low estrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346: 1582–8

    Google Scholar 

  44. Spitzer WO, Lewis MA, Heinemann LAJ, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996; 312: 83–8

    Article  PubMed  CAS  Google Scholar 

  45. Lewis MA, Heinemann LAJ, MacRae KD, et al. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. Contraception 1996; 54: 5–13

    Article  PubMed  CAS  Google Scholar 

  46. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346: 1593–6

    Article  PubMed  CAS  Google Scholar 

  47. Farmer RDT, Lawrenson RA, Thompson CR, et al. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–8

    Article  PubMed  CAS  Google Scholar 

  48. Bennet L, Odeberg H. Resistance to activated protein C, highly prevalent amongst users of oral contraceptives with venous thromboembolism. J Intern Med 1998; 244: 27–32

    Article  PubMed  CAS  Google Scholar 

  49. Vasilakis C, Jick SS, Jick H. The risk of venous thromboembolism in users of postcoital contraceptive pills. Contraception 1999; 59: 79–83

    Article  PubMed  CAS  Google Scholar 

  50. Farmer RDT, Todd JC, Lewis MA, et al. The risks of venous thromboembolic disease among German women using oral contraceptives: a database study. Contraception 1998; 57: 67–70

    Article  PubMed  CAS  Google Scholar 

  51. Todd JC, Lawrenson R, Farmer RDT, et al. Venous thromboembolic disease and combined oral contraceptives: a re-analysis of the MediPlus database. Hum Reprod 1999; 14: 1500–5

    Article  PubMed  CAS  Google Scholar 

  52. De Bruijn SFTM, Stam J, Vandenbroucke JP, et al. Increased risk of cerebral venous thrombosis with third-generation oral contraceptives [letter]. Lancet 1998; 351: 1404

    Article  PubMed  Google Scholar 

  53. Martinelli I, Taioli E, Palli D, et al. Risk of cerebral vein thrombosis and oral contraceptives [letter]. Lancet 1998; 352: 326

    Article  PubMed  CAS  Google Scholar 

  54. Weiss NS. Bias in studies ofvenous thromboembolism in relation to the use of new formulations of oral contraceptives. Contraception 1997; 55: 189–90

    Article  PubMed  CAS  Google Scholar 

  55. Vandenbroucke JP, Bloemenkamp KWM, Helmerhorst FM, et al. Risk of oral contraceptives and recency of market introduction. Contraception 1997; 55: 191–2

    Article  PubMed  CAS  Google Scholar 

  56. Inman WHW, Vessey MP, Westerholm B, et al. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. BMJ 1970; 2: 203–9

    Article  PubMed  CAS  Google Scholar 

  57. Böttiger LE, Boman G, Eklund G, et al. Oral contraceptives and thromboembolic disease: effects of lowering estrogen content. Lancet 1980; I: 1097–101

    Article  Google Scholar 

  58. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-μg estrogen preparations. BMJ 1980; 2: 1157–61

    Article  Google Scholar 

  59. Poulter NR, Chang CL, Marmot M, et al. Third-generation oral contraceptives and venous thrombosis [letter]. Lancet 1997; 349: 732

    Article  PubMed  CAS  Google Scholar 

  60. Lewis MA, MacRae KD, Kühl-Habich D, et al. The differential risk of oral contraceptives: the impact of full exposure history. Hum Reprod 1999; 14: 1493–9

    Article  PubMed  CAS  Google Scholar 

  61. Jick H, Jick S. Third-generation oral contraceptives and venous thrombosis. Lancet 1997; 349: 731–2

    Article  PubMed  CAS  Google Scholar 

  62. Farley TMM, Meirik O, Marmot MG, et al. Oral contraceptives and risk of venous thrombolism: impact of duration of use. Contraception 1998; 57: 61–4

    Article  PubMed  CAS  Google Scholar 

  63. Walker AM. Newer oral contraceptives and the risk of venous thromboembolism. Contraception 1998; 57: 169–81

    Article  PubMed  CAS  Google Scholar 

  64. Crook D, Godsland I. Safety evaluation of modern oral contraceptives. Contraception 1998; 57: 189–201

    Article  PubMed  CAS  Google Scholar 

  65. Winkler UH. Blood coagulation and oral contraceptives. Contraception 1998; 57: 203–9

    Article  PubMed  CAS  Google Scholar 

  66. Nichols M, Robinson G, Bounds W, et al. Effect of four combined oral contraceptives on blood pressure in the pill-free interval. Contraception 1993; 47: 367–76

    Article  PubMed  CAS  Google Scholar 

  67. Narkiewicz K, Graniero GR, D’Este D, et al. Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. Am J Hypertens 1995; 8: 249–53

    Article  PubMed  CAS  Google Scholar 

  68. Chasan-Taber L, Willet WC, Manson JE, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 1996; 94: 483–9

    Article  PubMed  CAS  Google Scholar 

  69. Cardoso F, Polónia J, Santos A, et al. Low-dose oral contraceptives and 24-hour ambulatory blood pressure. Int J Gyn Obstet 1997; 59: 237–43

    Article  CAS  Google Scholar 

  70. Rosing J, Tans G, Nicolaes GAF, et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233–8

    Article  PubMed  CAS  Google Scholar 

  71. Kluft C, de Maat MPM, Heinemann LAJ, et al. Importance of levonorgestrel dose in oral contraceptives for effects on coagulation. Lancet 1999; 354: 832–3

    PubMed  CAS  Google Scholar 

  72. Rosing J, Middledorp S, Curvers J, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036–40

    Article  PubMed  CAS  Google Scholar 

  73. Vandenbroucke JP, Rosendaal FR. End of the line for ‘third-generation-pill’ controversy? Lancet 1997; 349: 1113–4

    Article  PubMed  CAS  Google Scholar 

  74. Hannaford PC, Webb AMC on behalf of participants at an International Workshop. Evidence-Guided Prescribing of Combined Oral Contraceptives. Consensus Statement. Contraception 1996; 54: 125–9

    Article  PubMed  CAS  Google Scholar 

  75. Winkler UH. Role of screening for vascular disease in pill users: the homeostatic system. In: Hannaford PC, Webb AMC, editors. Evidence-guided prescribing of the pill. Carnforth, UK: Parthenon Publishing, 1996: 109–20

    Google Scholar 

  76. Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, et al. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996, 313; 1127–30

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The Centre for Primary Care Research and Epidemiology has received in the past unconditional grants from each of the COC manufacturers for its work. The author has been paid honoraria by all of the manufacturers for presentations at various meetings. The author was a paid consultant of the World Health Organization when he was rapporteur for a Scientific Group on cardiovascular disease and steroid hormone contraception.

Author information

Authors and Affiliations

  1. RCGP Centre for Primary Care Research and Epidemiology, Department of General Practice and Primary Care, Foresterhill Health Centre, Westburn Road, Aberdeen, AB25 2AY, Scotland

    Philip Hannaford

Authors
  1. Philip Hannaford
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip Hannaford.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hannaford, P. Cardiovascular Events Associated With Different Combined Oral Contraceptives. Drug-Safety 22, 361–371 (2000). https://doi.org/10.2165/00002018-200022050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200022050-00004

Keywords

Search

Navigation