Cardiovascular Drugs and Therapy

, Volume 20, Issue 1, pp 45–54

Safety of Nifedipine GITS in Stable Angina: The ACTION Trial

  • Philip A. Poole-Wilson
  • Bridget-Anne Kirwan
  • Zoltán Vokó
  • Sophie de Brouwer
  • Fred J. van Dalen
  • Jacobus Lubsen
  • on behalf of the ACTION Investigators
Clinical Trial
  • 213 Downloads

Summary

Aim: We describe the safety profile of nifedipine GITS as assessed from adverse events reported in the ACTION trial in which 7,665 patients with stable, symptomatic coronary artery disease were randomly assigned nifedipine GITS or placebo and followed for a mean of 4.9 years. Methods: All adverse events were coded using the COSTART coding dictionary. The incidence rate for each event was calculated as the number of patients with the event concerned divided by the total time ‘at risk’. Hazard ratios comparing nifedipine with placebo and their 95% confidence intervals were obtained by Cox proportional-hazards analysis. Results: As reported previously, nifedipine significantly reduced the incidence of cardiovascular events and procedures [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.83–0.95]. Apart from the known side effects of nifedipine, which include peripheral oedema, vasodilatation, hypotension, asthenia, constipation, leg cramps, non-specific respiratory complaints, impotence and polyuria, and which were reported more frequently in patients assigned nifedipine, the incidence rates of most other adverse events were similar. There were no differences in the occurrence of gastrointestinal haemorrhage, myocardial infarction and suicide. The rate of occurrence of death or new cancer excluding non-melanoma skin cancer for patients with no history of cancer at baseline was 2.53/100 patient years for patients assigned nifedipine and 2.37/100 patient years for patients assigned placebo (HR 1.06, 95% CI 0.93–1.22). Conclusion: Overall nifedipine GITS was well tolerated by patients with stable symptomatic angina.

Key Words

randomised controlled trial angina pectoris nifedipine GITS adverse events 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lenfant C. The calcium channel blocker scare. Lessons for the future. Circulation 1995;91:2855–2856.PubMedGoogle Scholar
  2. 2.
    Opie LH, Messerli FH. Nifedipine and mortality. Grave defects in the dossier. Circulation 1995;92:1068–1073.PubMedGoogle Scholar
  3. 3.
    Opie LH. Risks and benefits of calcium antagonists. Lancet 1995;346:961.CrossRefPubMedGoogle Scholar
  4. 4.
    Horton R. Spinning the risks and benefits of calcium antagonists. Lancet 1995;346:586–587.CrossRefPubMedGoogle Scholar
  5. 5.
    Poole-Wilson PA. The calcium antagonist controversy; implications beyond drug prescription. Eur Heart J 1996;17:1131–1133.PubMedGoogle Scholar
  6. 6.
    Kaplan NM. Do calcium antagonists cause myocardial infarction? Am J Cardiol 1996;77:81–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Kaplan NM. Do calcium antagonists cause death, gastrointestinal bleeding, and cancer? Am J Cardiol 1996;78:932–933.CrossRefPubMedGoogle Scholar
  8. 8.
    McMurray J, Murdoch D. Calcium-antagonist controversy: The long and short of it? Lancet 1997;349:585–586.CrossRefPubMedGoogle Scholar
  9. 9.
    Califf RM, Kramer JM. What have we learned from the calcium channel blocker controversy? Circulation 1998;97:1529–1531.PubMedGoogle Scholar
  10. 10.
    Lubsen J. The calcium channel antagonist debate: Recent developments. Eur Heart J 1998;19(Suppl I):I3–I7.PubMedGoogle Scholar
  11. 11.
    Stelfox HT, Chua G, O’Rourke K, Detsky AS. Conflict of interest in the debate over calcium-channel antagonists. N Engl J Med 1998;338:101–106.CrossRefPubMedGoogle Scholar
  12. 12.
    Psaty BM, Heckbert SR, Koepsell TD,et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620–625.CrossRefPubMedGoogle Scholar
  13. 13.
    Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326–1331.PubMedGoogle Scholar
  14. 14.
    Pahor M, Guralnik JM, Corti MC, Foley DJ, Carbonin P, Havlik RJ. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc 1995;43:1191–1197.PubMedGoogle Scholar
  15. 15.
    Furberg CD, Psaty BM. Should calcium antagonists be first-line agents in the treatment of cardiovascular disease? The public health perspective. Cardiovasc Drugs Ther 1996;10:463–466.CrossRefPubMedGoogle Scholar
  16. 16.
    Pahor M, Guralnik JM, Ferrucci L,et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996;348:493–497.CrossRefPubMedGoogle Scholar
  17. 17.
    Pahor M, Guralnik JM, Salive ME, Corti MC, Carbonin P, Havlik RJ. Do calcium channel blockers increase the risk of cancer? Am J Hypertens 1996;9:695–699.CrossRefPubMedGoogle Scholar
  18. 18.
    Pahor M, Guralnik JM, Furberg CD, Carbonin P, Havlik R. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996;347:1061–1065.CrossRefPubMedGoogle Scholar
  19. 19.
    Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998;158:33–39.CrossRefPubMedGoogle Scholar
  20. 20.
    Kaplan RC, Heckbert SR, Koepsell TD, Rosendaal FR, Psaty BM. Use of calcium channel blockers and risk of hospitalized gastrointestinal tract bleeding. Arch Intern Med 2000;160:1849–1855.CrossRefPubMedGoogle Scholar
  21. 21.
    Lindberg G, Bingefors K, Ranstam J, Rastam L, Melander A. Use of calcium channel blockers and risk of suicide: Ecological findings confirmed in population based cohort study. BMJ 1998;316:741–745.PubMedGoogle Scholar
  22. 22.
    Opie LH, Yusuf S, Kubler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: A critical analysis based on 100 studies. Prog Cardiovasc Dis 2000;43:171–196.CrossRefPubMedGoogle Scholar
  23. 23.
    Kizer JR, Kimmel SE. Epidemiologic review of the calcium channel blocker drugs. An up-to-date perspective on the proposed hazards. Arch Intern Med 2001;161:1145–1158.CrossRefPubMedGoogle Scholar
  24. 24.
    Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: An update. Am J Med 2004;116:35–43.CrossRefPubMedGoogle Scholar
  25. 25.
    Pitt B, Byington RP, Furberg CD,et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000;102:1503–1510.PubMedGoogle Scholar
  26. 26.
    Rehnqvist N, Hjemdahl P, Billing E,et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J 1996;17:76–81.PubMedGoogle Scholar
  27. 27.
    Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ. The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group. Eur Heart J 1996;17:96–103.PubMedGoogle Scholar
  28. 28.
    Dargie HJ, Ford I, Fox KM. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group. Eur Heart J 1996;17:104–112.PubMedGoogle Scholar
  29. 29.
    Poole-Wilson PA, Lubsen J, Kirwan BA,et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): Randomised controlled trial. Lancet 2004;364:849–857.CrossRefPubMedGoogle Scholar
  30. 30.
    Lubsen J, Poole-Wilson PA, Pocock SJ,et al. Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System. Eur Heart J 1998;19(Suppl I):I20–I32.PubMedGoogle Scholar
  31. 31.
    COSTART. In: Rockville MD (Eds.), Coding Symbols for Thesaurus of Adverse Reaction Terms, 5th ed. Food and Drug Administration, Center for Drug Evaluation and Research, 1995.Google Scholar
  32. 32.
    MRC/BHF. Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7–22.CrossRefGoogle Scholar
  33. 33.
    Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389.Google Scholar
  34. 34.
    Frison LJ, Pocock SJ. Linearly divergent treatment effects in clinical trials with repeated measures: Efficient analysis using summary statistics. Stat Med 1997;16:2855–2872.CrossRefPubMedGoogle Scholar
  35. 35.
    Lubsen J, Wagener G, Kirwan BA, de Brouwer S, Poole-Wilson PA. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: The ACTION trial. J Hypertens 2005;23:641–648.Google Scholar
  36. 36.
    Krakoff LR. Effectiveness of nifedipine gastrointestinal therapeutic system for treatment of hypertension: Results of the MATH Trial. J Cardiovasc Pharmacol 1993;21(Suppl 2):S14–S17.PubMedGoogle Scholar
  37. 37.
    Pfeffer MA, Swedberg K, Granger CB,et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet 2003;362:759–766.CrossRefPubMedGoogle Scholar
  38. 38.
    Shepherd J, Blauw GJ, Murphy MB,et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 2002;360:1623–1630.CrossRefPubMedGoogle Scholar
  39. 39.
    Sacks FM, Pfeffer MA, Moye LA,et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001–1009.CrossRefPubMedGoogle Scholar
  40. 40.
    Grossman E, Messerli FH, Goldbourt U. Carcinogenicity of antihypertensive therapy. Curr Hypertens Rep 2002;4:195–201.PubMedGoogle Scholar
  41. 41.
    Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium-channel blockers and risk of cancer. Lancet 1997;349:525–528.CrossRefPubMedGoogle Scholar
  42. 42.
    Rosenberg L, Rao RS, Palmer JR,et al. Calcium channel blockers and the risk of cancer. JAMA 1998;279:1000–1004.CrossRefPubMedGoogle Scholar
  43. 43.
    Stahl M, Bulpitt CJ, Palmer AJ, Beevers DG, Coles EC, Webster J. Calcium channel blockers, ACE inhibitors, and the risk of cancer in hypertensive patients: A report from the Department of Health Hypertension Care Computing Project (DHCCP). J Hum Hypertens 2000;14:299–304.Google Scholar
  44. 44.
    Beiderbeck-Noll AB, Sturkenboom MC, van der Linden PD,et al. Verapamil is associated with an increased risk of cancer in the elderly: The Rotterdam study. Eur J Cancer 2003;39:98–105.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Philip A. Poole-Wilson
    • 1
  • Bridget-Anne Kirwan
    • 2
    • 5
  • Zoltán Vokó
    • 3
  • Sophie de Brouwer
    • 2
  • Fred J. van Dalen
    • 2
  • Jacobus Lubsen
    • 2
    • 4
  • on behalf of the ACTION Investigators
  1. 1.Department of Cardiac MedicineImperial CollegeLondonUK
  2. 2.SOCAR ResearchNyonSwitzerland
  3. 3.The School of Public Health, Medical and Health Science CentreUniversity of DebrecenDebrecenHungary
  4. 4.The Department of Epidemiology and BiostatisticsErasmus Medical CentreRotterdamThe Netherlands
  5. 5.SOCAR Research SANyon 2Switzerland

Personalised recommendations