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Principal results from the international nifedipine GITS study: Intervention as a goal in hypertension treatment (INSIGHT)

M.J. Brown*,1, C.R. Palmer2, A. Castaigne3, P.W. de Leeuw4, G. Mancia5, T. Rosenthal6 and L.M. Ruilope7

a Clinical Pharmacology Unit, University of Cambridge, UK
b Centre for Applied Medical Statistics, University of Cambridge, Cambridge, U.K.
c Service de Cardiologie, Hôpital Henri Mondor, University of Paris, Paris, France
d University of Maastricht, Maastricht, The Netherlands
e Cattedra di Medicina Interna, University of Milan, Milan, Italy
f Hypertension Unit, The Chaim Sheba Medical Center, University of Tel Aviv, Tel Aviv, Israel
g Nephrology Department, Hospital 12 de Octobre, University of Madrid, Madrid, Spain

* Correspondence: Professor Morris J. Brown, Clinical Pharmacology Unit, Level 6, ACCI, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, U.K.

Abstract

Background We compared the effects of a long-acting calcium-channel blocker with a thiazide-amiloride combination on cardiovascular mortality and morbidity in patients with additional cardiovascular risk factors. The primary objective was to demonstrate 25% superiority of nifedipine GITS. A secondary objective was to establish non-inferiority compared with co-amilozide.

Methods A prospective, randomized, double-masked trial was carried out in Europe and Israel, involving 6321 patients of 55–80 years of age with hypertension (blood pressure mmHg or systolic ≥ 160 mmHg). Patients were also required to have at least one out of ten additional cardiovascular risk factors, such as diabetes or hypercholesterolaemia. Patients were assigned randomly to initial treatment with either nifedipine GITS (N), 30 mg, or co-amilozide (C) (hydrochlorothiazide, 25 mg, and amiloride, 2·5 mg), so that similar numbers of patients with each risk factor could be compared between the two drugs. Dose titration was principally by dose doubling, and addition of atenolol, 25–50 mg, or enalapril, 5–10 mg. Patients were followed for a mean period of 3 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, heart failure or stroke, Secondary outcome variables included death from any cause. Superiority analysis was of time to first event, by intention-to-treat. Non-inferiority analysis required the difference ({Delta}) in event-rate, and the 95% CI around {Delta}, to be <2% in patients remaining on randomized treatment.

Findings Mean blood pressure was decreased similarly in both treatment groups, from mmHg to () mmHg; 72% of patients were controlled on monotherapy. There were more withdrawals from the N group than from the C group, because of peripheral oedema in 8% and because of more serious adverse events (880 vs 776, ) in the C group. A primary end-point occurred in 200 (6·3%) of 3157 patients in the N group (18·2 events per 1000 patient-years) and in 182 (5·8%) of 3164 patients in the C group (16·5 events per 1000 patient-years; relative risk 1·1 [95% CI 0·90-1·3], ). Adding secondary variables, there were end-points in 383 (12·1%) of the N group (35·1 per 1000 patient-years), and 397 (12·7%) of the C group (36·5 per 1000 patient-years; relative risk 0·97 [95% CI 0·84-1·11], ). Deaths were predominantly non-vascular (N, 176 vs C, 172; ).

Interpretation The INSIGHT treatment regimens achieve optimal blood pressure control in most high-risk patients. This appears to be more important than choice of individual drugs in determining outcome in hypertension. Against a previous ‘gold standard’, nifedipine GITS was found to be effective in preventing cardiovascular or cerebrovascular complications, and may be regarded as appropriate first-line therapy in hypertension.

Key Words: Hypertension • nifedipine GITS • thiazide-amilozide • INSIGHT

Footnotes

This paper is based on our publication in the Lancet (July 2000)[22].

References

  1. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;325:827–838
  2. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994;330:1852–1857[Abstract/Free Full Text]
  3. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326–1331[Abstract/Free Full Text]
  4. Brown MJ, Castaigne A, Ruilope LM, et al. INSIGHT: International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment. J Hum Hypertens. 1996;10(Suppl 3):S157–S160
  5. http://www.insight-study.com, 2000 INSIGHT Website
  6. Treasure TB, MacRae K. Minimisation: the platinum standard for trials? Br Med J. 1998;317:362–363[Free Full Text]
  7. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41[Web of Science][Medline]
  8. Brown MJ, Castaigne A, De Leeuw PW, et al. Influence of diabetes and type of hypertension on the response to anti-hypertensive treatment. Hypertension. 2000;35:1038–1042[Abstract/Free Full Text]
  9. Neal B, MacMahon S. An overview of 37 randomised trials of blood pressure lowering agents among 270 000 individuals. Clin Exp Hypertens. 1999. p. 517–529
  10. Chalmers J, MacMahon S, Mancia G, et al. 1999 World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. Guidelines sub-committee. Clin Exp Hypertens. 1999;21:1009–1060
  11. Hansson L, Zanchetti A. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–1762[CrossRef][Web of Science][Medline]
  12. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart. 1998;80(Suppl 2):S1–S29 Cardiac Risk Assessor available athttp://www.hyp.ac.uk/bhs/risk.xls
  13. Arch Intern Med. 1997. p. 2413–2446
  14. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272–298[Abstract/Free Full Text]
  15. Staessen J, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757–764[CrossRef][Web of Science][Medline]
  16. Gong L, Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens. 1996;14:1237–1245[Web of Science][Medline]
  17. Liu L, Wang JG, Gong L, Liu G, Staessen JA. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. Systolic Hypertension in China (Syst-China) Collaborative Group. J Hypertens. 1998;16:1823–1829[CrossRef][Web of Science][Medline]
  18. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340:677–684[Abstract/Free Full Text]
  19. Pahor M, Guralnik JM, Corti M-C, et al. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc. 1995;43:1191–1197[Web of Science][Medline]
  20. Pahor M, Guralnik JM, Ferruci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet. 1996;348:493[CrossRef][Web of Science][Medline]
  21. Pahor M, Guralnik JM, Furberg CD, Carbonin P, Havlik RJ. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet. 1996;347:1061–1065[CrossRef][Web of Science][Medline]
  22. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with once-daily calcium channel blockade or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356:366[CrossRef][Web of Science][Medline]

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