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Meta-Analysis
. 2009 Oct 7;2009(4):CD006743.
doi: 10.1002/14651858.CD006743.pub2.

Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event

Marco I Perez  1 , Vijaya M Musini, James M Wright
Affiliations
Meta-Analysis

Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event

Marco I Perez et al. Cochrane Database Syst Rev. .

Abstract

Background: Acute cardiovascular events represent a therapeutic challenge. Blood pressure lowering drugs are commonly used and recommended in the early phase of these settings. This review analyses randomized controlled trial (RCT) evidence for this approach.

Objectives: To determine the effect of immediate and short-term administration of anti-hypertensive drugs on all-cause mortality, total non-fatal serious adverse events (SAE) and blood pressure, in patients with an acute cardiovascular event, regardless of blood pressure at the time of enrollment.

Search strategy: MEDLINE, EMBASE, and Cochrane clinical trial register from Jan 1966 to February 2009 were searched. Reference lists of articles were also browsed. In case of missing information from retrieved articles, authors were contacted.

Selection criteria: Randomized controlled trials (RCTs) comparing anti-hypertensive drug with placebo or no treatment administered to patients within 24 hours of the onset of an acute cardiovascular event.

Data collection and analysis: Two reviewers independently extracted data and assessed risk of bias. Fixed effects model with 95% confidence intervals (CI) were used. Sensitivity analyses were also conducted.

Main results: Sixty-five RCTs (N=166,206) were included, evaluating four classes of anti-hypertensive drugs: ACE inhibitors (12 trials), beta-blockers (20), calcium channel blockers (18) and nitrates (18). Acute stroke was studied in 6 trials (all involving CCBs). Acute myocardial infarction was studied in 59 trials. In the latter setting immediate nitrate treatment (within 24 hours) reduced all-cause mortality during the first 2 days (RR 0.81, 95%CI [0.74,0.89], p<0.0001). No further benefit was observed with nitrate therapy beyond this point. ACE inhibitors did not reduce mortality at 2 days (RR 0.91,95%CI [0.82, 1.00]), but did after 10 days (RR 0.93, 95%CI [0.87,0.98] p=0.01). No other blood pressure lowering drug administered as an immediate treatment or short-term treatment produced a statistical significant mortality reduction at 2, 10 or >/=30 days. There was not enough data studying acute stroke, and there were no RCTs evaluating other acute cardiovascular events.

Authors' conclusions: Nitrates reduce mortality (4-8 deaths prevented per 1000) at 2 days when administered within 24 hours of symptom onset of an acute myocardial infarction. No mortality benefit was seen when treatment continued beyond 48 hours. Mortality benefit of immediate treatment with ACE inhibitors post MI at 2 days did not reach statistical significance but the effect was significant at 10 days (2-4 deaths prevented per 1000). There is good evidence for lack of a mortality benefit with immediate or short-term treatment with beta-blockers and calcium channel blockers for acute myocardial infarction.

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Conflict of interest statement

None.

Figures

1
1
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Forest plot of comparison: 4 Nitrates, outcome: 4.1 All‐cause mortality at 2 days.
5
5
Forest plot of comparison: 4 Nitrates, outcome: 4.2 All‐cause mortality at 10 days.
6
6
Forest plot of comparison: 4 Nitrates, outcome: 4.3 All‐cause mortality at ≥30 days.
7
7
Forest plot of comparison: 1 ACEi, outcome: 1.1 All‐cause mortality at 2 days.
8
8
Forest plot of comparison: 1 ACEi, outcome: 1.2 All‐cause mortality at 10 days.
9
9
Forest plot of comparison: 2 BB, outcome: 2.1 All‐cause mortality at 2 days.
10
10
Forest plot of comparison: 2 BB, outcome: 2.3 All‐cause mortality at 10 days.
11
11
Forest plot of comparison: 2 BB, outcome: 2.4 All‐cause mortality at ≥30 day.
12
12
Forest plot of comparison: 3 CCB, outcome: 3.1 All‐cause mortality at 2 days.
13
13
Forest plot of comparison: 3 CCB, outcome: 3.2 All‐cause mortality at 10 days.
14
14
Forest plot of comparison: 2 BB, outcome: 2.4 Weighted mean change in Systolic Blood pressure during first 24 hours.
15
15
Forest plot of comparison: 2 BB, outcome: 2.5 Weighted mean change in Diastolic Blood pressure during first 24 hours.
16
16
Forest plot of comparison: 2 BB, outcome: 2.6 Weighted mean change in heart rate during first 24 hours.
17
17
Forest plot of comparison: 3 CCB, outcome: 3.6 Weighted mean change in heart rate during first 24 hours.
18
18
Forest plot of comparison: 4 Nitrates, outcome: 4.4 Weighted mean change in Systolic Blood pressure during first 24 hours.
19
19
Forest plot of comparison: 4 Nitrates, outcome: 4.8 Sensitivity analysis mortality 0‐2 vs. 3‐10 days vs. day 11 to end of treatment (35‐42 days).
20
20
Forest plot of comparison: 1 ACEi, outcome: 1.7 Sensitivity analysis: mortality 0‐2 vs. 3‐10 days vs day 11 to end of treatment (35‐42 days).
1.1
1.1. Analysis
Comparison 1 Nitrates, Outcome 1 All‐cause mortality at 2 days.
1.2
1.2. Analysis
Comparison 1 Nitrates, Outcome 2 All‐cause mortality at 10 days.
1.3
1.3. Analysis
Comparison 1 Nitrates, Outcome 3 All‐cause mortality at ≥30 days.
1.4
1.4. Analysis
Comparison 1 Nitrates, Outcome 4 Weighted mean change in Systolic Blood pressure during first 24 hours.
1.5
1.5. Analysis
Comparison 1 Nitrates, Outcome 5 Weighted mean change in Diastolic Blood pressure during first 24 hours.
1.6
1.6. Analysis
Comparison 1 Nitrates, Outcome 6 Weighted mean change in heart rate during first 24 hours.
1.7
1.7. Analysis
Comparison 1 Nitrates, Outcome 7 Sensitivity analysis mortality 0‐2 vs. 3‐10 days vs. day 11 to end of treatment (35‐42 days).
2.1
2.1. Analysis
Comparison 2 ACEi, Outcome 1 All‐cause mortality at 2 days.
2.2
2.2. Analysis
Comparison 2 ACEi, Outcome 2 All‐cause mortality at 10 days.
2.3
2.3. Analysis
Comparison 2 ACEi, Outcome 3 Sensitivity analysis: mortality 0‐2 vs. 3‐10 days vs day 11 to end of treatment (35‐42 days).
3.1
3.1. Analysis
Comparison 3 BB, Outcome 1 All‐cause mortality at 2 days.
3.2
3.2. Analysis
Comparison 3 BB, Outcome 2 All‐cause mortality at 10 days.
3.3
3.3. Analysis
Comparison 3 BB, Outcome 3 All‐cause mortality at ≥30 day.
3.4
3.4. Analysis
Comparison 3 BB, Outcome 4 Weighted mean change in Systolic Blood pressure during first 24 hours.
3.5
3.5. Analysis
Comparison 3 BB, Outcome 5 Weighted mean change in Diastolic Blood pressure during first 24 hours.
3.6
3.6. Analysis
Comparison 3 BB, Outcome 6 Weighted mean change in heart rate during first 24 hours.
3.7
3.7. Analysis
Comparison 3 BB, Outcome 7 Sensitivity analysis: mortality at 2 days, according to trial design.
4.1
4.1. Analysis
Comparison 4 CCB, Outcome 1 All‐cause mortality at 2 days.
4.2
4.2. Analysis
Comparison 4 CCB, Outcome 2 All‐cause mortality at 10 days.
4.3
4.3. Analysis
Comparison 4 CCB, Outcome 3 All‐cause mortality at ≥30 days.
4.4
4.4. Analysis
Comparison 4 CCB, Outcome 4 Weighted mean change in Systolic Blood pressure during first 24 hours.
4.5
4.5. Analysis
Comparison 4 CCB, Outcome 5 Weighted mean change in Diastolic Blood pressure during first 24 hours.
4.6
4.6. Analysis
Comparison 4 CCB, Outcome 6 Weighted mean change in heart rate during first 24 hours.
4.7
4.7. Analysis
Comparison 4 CCB, Outcome 7 Sensititity analysis: mortality at 10 days, according underlying CVE.
4.8
4.8. Analysis
Comparison 4 CCB, Outcome 8 Sensitivity Analysis: mortality at 10 days, according sub‐class of CCB in AMI.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

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Paci 1989 {published data only}
    1. Paci A, Ottaviano P, Trenta A, Iannone G, Santis L, Lancia G, et al. Nimodipine in acute ischemic stroke: a double‐blind controlled study. Acta neurologica Scandinavica. 1989;80:282‐6. - PubMed
Peter 1978 {published data only}
    1. Peter T. Reduction of enzyme levels by propranolol after acute myocardial infarction. Circulation 1978;57(6):1091‐1095. - PubMed
Pimenta 1985 {published data only}
    1. Pimenta J, Pereira CB. Nifedipine in acute myocardial infarction: effect on infarct size and clinical course [Nifedipina na fase aguda do infarto do mioc?rdio: a??o sobre a massa infartada e evolu??o clÍnica]. Rev. med. IAMSPE 1985;16(1/2):11‐16.
Pizzetti 2001 {published data only}
    1. Pizzetti G, Mailhac A, Li VL, Di MF, Lu C, Margonato A, Chierchia SL. Beneficial effects of diltiazem during myocardial reperfusion: a randomized trial in acute myocardial infarction. Italian heart journal 2001;2:757‐765. - PubMed
PRACTICAL 1994 {published data only}
    1. Foy SG, Crozier IG, Turner JG, Richards AM, Frampton CM, Nicholls MG, et al. Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the "PRACTICAL" study). The American journal of cardiology. 1994;73:1180‐6. - PubMed
Salathia 1985 {published data only}
    1. Salathia KS, Barber JM, McIlmoyle EL, Nicholas J, Evans AE, Elwood JH, et al. Very early intervention with metoprolol in suspected acute myocardial infarction. European Heart Journal 1985;6(3):190‐8. - PubMed
Schulman 1995 {published data only}
    1. Schulman SP, Weiss JL, Becker LC, Guerci AD, Shapiro EP, Chandra NC, Siu C, Flaherty JT, Coombs V, Taube JC. Effect of early enalapril therapy on left ventricular function and structure in acute myocardial infarction. Am J Cardiol 1995;76(11):764‐70. - PubMed
Sirnes 1984 {published data only}
    1. Sirnes PA, Overskeid K, Pedersen TR, Bathen J, Drivenes A, Froland GS, Kjekshus JK, Landmark K, Rokseth R, Sirnes KE. Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: the Norwegian Nifedipine Multicenter Trial. Circulation 1984;70:638‐644. - PubMed
Theroux 1998 {published data only}
    1. Theroux P. Intravenous diltiazem in acute myocardial infarction. Diltiazem as adjunctive therapy to activase (DATA) trial. Journal of the American College of Cardiology 1998;32(3):620‐628. - PubMed
TIMI‐IIB 1991 {published data only}
    1. Guerci AD. Acute intravenous beta blockade as an adjunct to thrombolytic therapy. Clinical cardiology 1991;14:37‐9.
    1. TIMI‐II, Roberts R. Immediate versus deferred beta‐blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II‐B Study.[see comment]. Circulation 1991;83(2):422‐437. - PubMed
Tonkin 1981 {published data only}
    1. Tonkin AM, Joel SE, Reynolds JL, Aylward PE, Heddle WF, McRitchie RJ, West MJ, Chalmers JP. beta‐Blockade in acute myocardial infarction. Inability of relatively late administration to influence infarct size and arrhythmias. Medical Journal of Australia 1981;2(3):145‐146. - PubMed
Van‐de 1993 {published data only}
    1. Heidb chel, Tack J, Vanneste L, Ballet A, Ector H, Van‐de Werf F. Significance of arrhythmias during the first 24 hours of acute myocardial infarction treated with alteplase and effect of early administration of a beta‐blocker or a bradycardiac agent on their incidence. Circulation. 1994;89:1051‐9. - PubMed
    1. Van‐de Werf F, Janssens L, Brzostek T, Mortelmans L, Wackers FJ, Willems GM, et al. Short‐term effects of early intravenous treatment with a beta‐adrenergic blocking agent or a specific bradycardiac agent in patients with acute myocardial infarction receiving thrombolytic therapy. Journal of the American College of Cardiology. 1993;22:407‐16. - PubMed
VENUS 2001 {published data only (unpublished sought but not used)}
    1. Horn J, de‐Haan RJ, Vermeulen M, Limburg M. Very Early Nimodipine Use in Stroke (VENUS): a randomized, double‐blind, placebo‐controlled trial. Stroke 2001;32:461‐465. - PubMed
von Essen 1982 {published data only}
    1. Essen R, Merx W, Neis W, Ritz R. Effect of metoprolol on infarct size after acute myocardial infarction (a double‐blind study). Deutsche Medizinische Wochenschrift 1982;107(34):1267‐73. - PubMed
Wagner 2002 {published data only}
    1. Wagner A, Herkner H, Schreiber W, Bur A, Woisetschl ger C, Stix G, et al. Ramipril prior to thrombolysis attenuates the early increase of PAI‐1 in patients with acute myocardial infarction. Thrombosis and haemostasis. 2002;88:180‐5. - PubMed
Yusuf 1983 {published data only}
    1. Yusuf S S. Reduction in infarct size, arrhythmias and chest pain by early intravenous beta blockade in suspected acute myocardial infarction. Circulation 1983;67(6 Pt2):I32‐I41. - PubMed
Zannad 1988 {published data only}
    1. Zannad F, Amor M, Karcher G, Maurin P, Ethevenot G, Sebag C, Bertrand A, Pernot C, Gilgenkrantz JM. Effect of diltiazem on myocardial infarct size estimated by enzyme release, serial thallium‐201 single‐photon emission computed tomography and radionuclide angiography. Am J Cardiol 1988;61(15):1172‐7. - PubMed
Zharov 1991 {published data only}
    1. Zharov EI, Vertkin AL, Martynov AI, Salnikov SN. Comparative evaluation of intravenous isosorbide dinitrate and nitroglycerin in patients with acute myocardial infarction. Cardiology 1991;79(Suppl 2):63‐9. - PubMed

References to studies excluded from this review

Annane 1996 {published data only}
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    1. Annane D, Bellissant E, Pussard E, Asmar R, Lacombe F, Lanata E, et al. Placebo‐controlled, randomized, double‐blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema. Circulation 1996;94(6):1316‐24. - PubMed
Ardissino 1997 {published data only}
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Azancot 1982 {published data only}
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Azcona 1990 {published data only}
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Barber 1976 {published data only}
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Basu 1997 {published data only}
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Blanc 1989 {published data only}
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Briant 1970 {published data only}
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Bussmann 1984 {published data only}
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CATS 1994 {published data only}
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CHHIPS 2005 {published data only}
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Davalos 1992 {published data only}
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DAVIT I 1984 {published data only}
    1. Anonymous. Abrupt withdrawal of verapamil in ischaemic heart disease. The Danish Study Group on Verapamil in Myocardial Infarction. European Heart Journal. 1984;5:529‐32. - PubMed
    1. Anonymous. Verapamil in acute myocardial infarction. The Danish Multicentre Study Group. Clinical and experimental pharmacology & physiology.Supplement. 1982;6:89‐96. - PubMed
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    1. Danish. Verapamil in acute myocardial infarction [THE DANISH STUDY GROUP]. EUR HEART J 1984;5:516‐28. - PubMed
    1. Fischer Hansen J. Verapamil in acute myocardial infarction. American Journal of Cardiology 1984;54(11):24E‐8E. - PubMed
Emanuelsson 1984 {published data only}
    1. Emanuelsson H, Herlitz J, Hjalmarson A, Holmberg S, Waagstein F, Waldenstr"m A, et al. Hemodynamic and clinical findings after combined therapy with metoprolol and nifedipine in acute myocardial infarction. Clinical Cardiology. 1984;7:425‐32. - PubMed
EMIP 1994 {published data only}
    1. EMIP BB, Leizorovicz A, Alberque. Pre‐hospital treatment of patients with suspected acute myocardial infarction using a beta‐blocking agent: A double‐blind feasibility study;EMIP‐BB Pilot Study Group. CLIN.TRIALS META ANALYS. 1994;29:125‐38. - PubMed
Evemy 1978 {published data only}
    1. Evemy KL, Pentecost BL. Intravenous and oral practolol in the acute stages of myocardial infarction. Eur J Cardiol 1978;7(5‐6):391‐8. - PubMed
Eveson 2007 {published data only}
    1. Eveson DJ, Robinson TG, Potter JF. Lisinopril for the treatment of hypertension within the first 24 hours of acute ischemic stroke and follow‐up. American Journal of Hypertension : Journal of the American Society of Hypertension 2007;20(3):270‐7. - PubMed
FAMIS 1998 {published data only}
    1. Borghi C. Short‐ and long‐term effects of early fosinopril administration in patients with acute anterior myocardial infarction undergoing intravenous thrombolysis: results from the Fosinopril in Acute Myocardial Infarction Study. FAMIS Working Party. American Heart Journal 1998;136(2):213‐225. - PubMed
    1. Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E. Post acute myocardial infarction: the Fosinopril in Acute Myocardial Infarction Study (FAMIS). American journal of hypertension : journal of the American Society of Hypertension. 1997;10:247S‐54S. - PubMed
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Franke 1996 {published data only}
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French 1999 {published data only}
    1. French JK, Amos DJ, Williams BF, Cross DB, Elliott JM, Hart HH, et al. Effects of early captopril administration after thrombolysis on regional wall motion in relation to infarct artery blood flow. Journal of the American College of Cardiology. 1999;33:139‐45. - PubMed
Gardtman 1999 {published data only}
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Gebalska 2000 {published data only}
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Gelmers 1984 {published data only}
    1. Gelmers HJ. Calcium‐channel blockers: effects on cerebral blood flow and potential uses for acute stroke. The American journal of cardiology. 1985;55:144B‐8B. - PubMed
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Gerstenblith 1982 {published data only}
    1. Gerstenblith G, Ouyang P, Achuff SC, Bulkley BH, Becker LC, Mellits ED, et al. Nifedipine in unstable angina: a double‐blind, randomized trial. The New England journal of medicine. 1982;306:885‐9. - PubMed
GISSI‐3p 1994 {published data only}
    1. Latini R, Avanzini F, Nicolao A, Rocchetti M. Effects of lisinopril and nitroglycerin on blood pressure early after myocardial infarction: the GISSI‐3 pilot study. Clinical pharmacology and therapeutics. 1994;56:680‐92. - PubMed
Gonzalez‐Fernandez 1993 {published data only}
    1. Altieri PI, Gonzalez R, De MWC, Escobales N. Enalapril (converting enzyme inhibitor) reduces the degree of left ventricular remodeling and reduces the incidence of ventricular arrhythmias in ischemic heart disease. NEW TRENDS ARRHYTHMIAS. 1993;9:615‐32.
    1. Gonzalez‐Fernandez RA, Altieri PI, Lugo JE, Fernandez Martnez J. Effects of enalapril on ventricular volumes and neurohumoral status after inferior wall myocardial infarction. The American journal of the medical sciences. 1993;305:216‐21. - PubMed
Gordon 1984 {published data only}
    1. Gordon GD, Mabin TA, Isaacs S, Lloyd EA, Eichler HG, Opie LH. Hemodynamic effects of sublingual nifedipine in acute myocardial infarction. American Journal of Cardiology 1984;53(9):1228‐1232. - PubMed
Gottlieb 1986 {published data only}
    1. Gottlieb SO, Weisfeldt ML, Ouyang P, Achuff SC, Baughman KL, Traill TA, et al. Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double‐blind, placebo‐controlled trial. Circulation. 1986;73:331‐7. - PubMed
Gottlieb 1988 {published data only}
    1. Gottlieb SO, Becker LC, Weiss JL, Shapiro EP, Chandra NC, Flaherty JT, et al. Nifedipine in acute myocardial infarction: an assessment of left ventricular function, infarct size, and infarct expansion. A double blind, randomised, placebo controlled trial. British heart journal. 1988;59:411‐8. - PMC - PubMed
Gupta 1984 {published data only}
    1. Gupta RC, Butaney B, Narang NK. Effect of IV propranolol on the extent of myocardial ischaemic injury in patients with acute anterior myocardial infarction. Proceeding of 39th Joint Annual Conference of Association of Physicians of India. Hyderabad, 1984.
Gupta 1985 {published data only}
    1. Gupta RC, Sharma SK, Arora YK, Tripathi K. Reduction of infarct size by early use of oral propranolol and verapamil in acute myocardial infarction. Journal of the Association of Physicians of India 1985;33(9):577‐80. - PubMed
Hamilton 1996 {published data only}
    1. Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril. Academic emergency medicine : official.journal of the Society for Academic Emergency Medicine. 1996;3:205‐12. - PubMed
    1. Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril.[see comment]. Academic Emergency Medicine 1996;3(3):205‐212. - PubMed
Haude 1991 {published data only}
    1. Haude M, Erbel R, Steffen W, Tschollar W, Meyer J. Sublingual administration of captopril in patients with acute myocardial ischemia. Clinical Cardiology. 1991;14:463‐8. - PubMed
HEART 1997 {published data only}
    1. Pfeffer MA, Greaves SC, Arnold JM, Glynn RJ, LaMotte FS, Lee RT, et al. Early versus delayed angiotensin‐converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial. Circulation 1997;95(12):2643‐51. - PubMed
    1. Pfeffer MA, Hennekens CH. When a question has an answer: rationale for our early termination of the HEART Trial. American Journal of Cardiology 1995;75(16):1173‐5. - PubMed
    1. Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation. 1997;96:442‐7. - PubMed
HINT 1986 {published data only}
    1. HINT. Early treatment of unstable angina in the coronary care unit: a randomised, double blind, placebo controlled comparison of recurrent ischaemia in patients treated with nifedipine or metoprolol or both. Report of The Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group. British heart journal 1986;56(5):400‐13. - PMC - PubMed
    1. Lubsen J, Tijssen JG. Efficacy of nifedipine and metoprolol in the early treatment of unstable angina in the coronary care unit: findings from the Holland Interuniversity Nifedipine/metoprolol Trial (HINT). The American journal of cardiology. 1987;60:18A‐25A. - PubMed
    1. Tijssen JG, Lubsen J. Early treatment of unstable angina with nifedipine and metoprolol‐‐the HINT trial. Journal of cardiovascular pharmacology. 1988;12 Suppl 1:S71‐7. - PubMed
    1. Tijssen JG, Lubsen J. Nifedipine and metoprolol in unstable angina: findings from the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT). Journal of cardiovascular pharmacology. 1987;10 Suppl 2:S15‐22. - PubMed
    1. Wall EE, Kerkkamp HJ, Simoons ML, Rijk PP, Reiber JH, Bom N, et al. Influence of nifedipine on left ventricular perfusion and function in patients with unstable angina: evaluation with radionuclide techniques. European journal of nuclear medicine 1986;11(11):428‐33. - PubMed
Jaffe 1987 {published data only}
    1. Jaffe AS, Biello DR, Sobel BE, Geltman EM. Enhancement of metabolism of jeopardized myocardium by nifedipine. International journal of cardiology 1987;15(1):77‐89. - PubMed
Just 1986 {published data only}
    1. Just H, Heidelbach I, Jackle B, Wollschlager H. Nifedipine in acute myocardial infarction: Can a myocardial protective effect be demonstrated in a double blind placebo controlled study?. INTENSIVMEDIZIN. 1986;23:159‐64.
Kahler 1995 {published data only}
    1. Kahler J, Schneider CA, Ambrosius U, Neff U, Klepzig JH, Bussmann WD. Gallopamil in acute myocardial infarction. Herz Kreislauf. 1995;27:370‐4.
Karlberg 1998 {published data only}
    1. Karlberg KE, Saldeen T, Wallin R, Henriksson P, Nyquist O, Sylven C. Intravenous nitroglycerin reduces ischaemia in unstable angina pectoris: a double‐blind placebo‐controlled study. Journal of Internal Medicine 1998;243(1):25‐31. - PubMed
Kolettis 1983 {published data only}
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Kumada 1995 {published data only}
    1. Kumada T, Kawai C, Sasayama S, Kinoshita M, Kawamura K, Kusukawa R, et al. Clinical efficacy of nicardipine by intravenous infusion in patients with acute heart failure. A multicenter randomized double‐blind placebo‐controlled trial. Japanese Pharmacology and Therapeutics. 1995;23:163‐86.
Lejemtel 1993 {published data only}
    1. Lejemtel T, Hochman JS, Edelstein R. Captopril before reperfusion in acute myocardial infarction: the CAPTIN experience. Journal of the American College of Cardiology 1993;21:371A.
Lloyd 1988 {published data only}
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Loogna 1985 {published data only}
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Macleod 1980 {published data only}
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Manolis 1999 {published data only}
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Matias‐Gutierrez 1992 {published data only}
    1. Matias‐Gutierrez J, Molto JM, Galiano L, Insa R, Falip R, Martin R. Pilot double blind placebo controlled trial of nicardipine versus placebo for cognitive impairment in minor stroke patients. Journal of neurology 1992;239:S39.
McGrath 1986 {published data only}
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Morris 1995 {published data only}
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Mueller 1980 {published data only}
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Murdock 1990 {published data only}
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Oldroyd 1991 {published data only}
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Oshima 1997 {published data only}
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Osuna 1985 {published data only}
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Ramsdale 1988 {published data only}
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Reinert 2004 {published data only}
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Renard 1987 {published data only}
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Reynolds 1972 {published data only}
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Schrader 2003 {published data only}
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Sloman 1967 {published data only}
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SMILE 1995 {published data only}
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