[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.163.129.96. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Table 1. 
Observational Studies in Hypertension*
Observational Studies in Hypertension*
Table 2. 
Clinical Trials and Overviews in Hypertension*
Clinical Trials and Overviews in Hypertension*
Table 3. 
Clinical Trials and Overviews in Acute Coronary Syndromes*
Clinical Trials and Overviews in Acute Coronary Syndromes*
Table 4. 
Clinical Trials and Overviews in Stable Angina*
Clinical Trials and Overviews in Stable Angina*
Table 5. 
Clinical Trials in Left Ventricular Dysfunction*
Clinical Trials in Left Ventricular Dysfunction*
Table 6. 
Studies Assessing Cancer Risk*
Studies Assessing Cancer Risk*
Table 7. 
Studies Assessing Bleeding Risk*
Studies Assessing Bleeding Risk*
1.
Fagan  TC Calcium antagonists and mortality: another case of the need for clinical judgment [editorial]. Arch Intern Med. 1995;1552145Article
2.
Poole-Wilson  PA The calcium antagonist controversy: implications beyond drug prescription [editorial]. Eur Heart J. 1996;171131- 1133Article
3.
Kaplan  NM Do calcium antagonists cause death, gastrointestinal bleeding and cancer [editorial]? Am J Cardiol. 1996;78932- 933Article
4.
Not Available, Calcium-channel blockers: managing uncertainty [editorial]. Lancet. 1996;348487Article
5.
Dargie  HJFord  I Calcium-channel blockers and the clinician [editorial]. Lancet. 1996;348488- 489Article
6.
McMurray  JMurdoch  D Calcium-antagonist controversy: the long and short of it [editorial]? Lancet. 1997;349585- 586Article
7.
Califf  RMKramer  JM What have we learned from the calcium channel blocker controversy [editorial]? Circulation. 1998;971529- 1531Article
8.
Stanton  AV Calcium channel blockers: the jury is still out on whether they cause heart attacks and suicide [editorial]. BMJ. 1998;3161471- 1473Article
9.
Lubsen  J The calcium channel antagonist debate: recent developments. Eur Heart J. 1998;19 (Suppl I) I3- I7
10.
Manolio  TACutler  JAFurberg  CD  et al.  Trends in pharmacologic management of hypertension in the United States. Arch Intern Med. 1995;155829- 837Article
11.
Psaty  BMHeckbert  SRKoepsell  TD  et al.  The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274620- 625Article
12.
Furberg  CDPsaty  BMMeyer  JV Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;921326- 1331Article
13.
Furberg  CDPsaty  BM Corrections to the nifedipine meta-analysis. Circulation. 1996;931475- 1476
14.
Pahor  MGuralnik  JMCorti  MCFoley  DJCarbonin  PHavlik  RJ Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc. 1995;431191- 1197
15.
Pahor  MGuralnik  JMSalive  MECorti  MCCarbonin  PHavlik  RJ Do calcium-channel blockers increase the risk of cancer? Am J Hypertens. 1996;9695- 699Article
16.
Pahor  MGuralnik  JMFerrucci  L  et al.  Calcium-channel blockade and incidence of cancer in aged populations. Lancet. 1996;348493- 497Article
17.
Hardell  LFredrikson  MAxelson  O Case-control study in colon cancer regarding previous diseases and drug intake. Int J Oncol. 1995;8439- 445
18.
Wagenknecht  LEFurberg  CDHammon  JWLegault  CTroost  BT Surgical bleeding: unexpected effect of a calcium antagonist. BMJ. 1995;310776- 777Article
19.
Legault  CFurberg  CDWagenknecht  LE  et al.  Nimodipine neuroprotection in cardiac valve replacement: report of an early terminated trial. Stroke. 1996;27593- 598Article
20.
Pahor  MGuralnik  JMFurberg  CDCarbonin  PHavlik  RJ Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet. 1996;3471061- 1065Article
21.
Lindberg  GBingefors  KRanstam  JRastam  LMelander  A Use of calcium-channel blockers and risk of suicide: ecological findings confirmed in population-based cohort study. BMJ. 1998;316741- 745Article
22.
Freher  MChallapalli  SPinto  JVSchwartz  JBonow  ROGheorgiode  M Current status of calcium channel blockers in patients with cardiovascular disease. Curr Probl Cardiol. 1999;24236- 240Article
23.
Abernethy  DRSchwartz  JB Calcium antagonist drugs. N Engl J Med. 1999;3411447- 1457Article
24.
Kizer  JRKimmel  SE The calcium-channel blocker controversy: historical perspective and lessons for future pharmacotherapies: an International Society of Pharmacoepidemiology "Hot Topic." Pharmacoepidemiol Drug Saf. 2000;925- 36Article
25.
Lenfant  C The calcium channel blocker scare: lessons for the future [editorial]. Circulation. 1995;912855- 2856Article
26.
Strom  BLMelmon  KL The use of pharmacoepidemiology to study beneficial drug effects. Strom  BLed.Pharmacoepidemiology 2nd ed. New York, NY John Wiley & Sons Inc1994;449- 467
27.
Walker  AMStampfer  MJ Observational studies of drug safety [editorial]. Lancet. 1996;348489Article
28.
Taubes  G Epidemiology faces its limits. Science. 1995;269164- 169Article
29.
Aursnes  ILitleskare  IFroyland  HAbdelnoor  M Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Press. 1995;4157- 163Article
30.
Jick  HVasilakis  CDerby  LE Antihypertensive drugs and fatal myocardial infarction in persons with uncomplicated hypertension. Epidemiology. 1997;8446- 448Article
31.
Leader  SGMallick  RBriggs  NC Myocardial infarction in newly diagnosed hypertensive Medicaid patients free of coronary heart disease and treated with calcium channel blockers. Am J Med. 1997;102150- 157Article
32.
Alderman  MHCohen  HRoque  RMadhavan  S Effect of long-acting and short-acting calcium antagonists on cardiovascular outcomes in hypertensive patients. Lancet. 1997;349594- 598Article
33.
Abascal  VMLarson  MGEvans  JCBlohm  ATPoli  KLevy  D Calcium antagonists and mortality risk in men and women with hypertension in the Framingham heart study. Arch Intern Med. 1998;1581882- 1886Article
34.
Michels  KBRosner  BAManson  JE  et al.  Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women: the Nurses' Health Study. Circulation. 1998;971540- 1548Article
35.
Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension, Effects of calcium antagonists on the risks of coronary heart disease, cancer and bleeding. J Hypertens. 1997;15105- 115
36.
Grossman  EMesserli  FH Effect of calcium antagonists on plasma norepinephrine levels, heart rate and blood pressure. Am J Cardiol. 1997;801453- 1458Article
37.
The GLANT Study Group, A 12-month comparison of ACE-inhibitor and Ca-antagonist therapy in mild to moderate essential hypertension: the GLANT Study. Hypertens Res. 1995;18235- 244Article
38.
Borhani  NOMercuri  MBorhani  PA  et al.  Final outcome results of the multicenter isradipine diuretic atherosclerosis study. JAMA. 1996;276785- 791Article
39.
Stason  WBSchmid  CHNiedzwiecki  D  et al.  Safety of nifedipine in patients with hypertension: a meta-analysis. Hypertension. 1997;30 ((part 1)) 7- 14Article
40.
Cheng-Du Hypertension Intervention Collaborative Group, Randomised trial of treatment with nifedipine in hypertensive patients. Chin J Cardiol. 1994;22201- 205
41.
Gong  LZhang  WZhu  Y  et al.  Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens. 1996;141237- 1245Article
42.
Liu  LWang  JGGong  LLiu  GStaessen  JA Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens. 1998;161823- 1829Article
43.
Staessen  JAFagard  RLutgarde  T  et al.  Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350757- 764Article
44.
Hansson  LLindholm  LHEkbom  T  et al.  Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity: the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;3541751- 1756Article
45.
Hansson  LHedner  TLund-Johansen  P  et al.  Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study. Lancet. 2000;356359- 365Article
46.
Brown  MJPalmer  CRCastaigne  A  et al.  Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356366- 372Article
47.
Byington  RPCraven  TEFurberg  CDPahor  M Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events [letter]. Lancet. 1997;3501075- 1076Article
48.
Tatti  PPahor  MByington  RP  et al.  Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21597- 603Article
49.
Estacio  ROJeffers  BWHiatt  WRBiggerstaff  SLGifford  NSchner  RW The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non–insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338645- 652Article
50.
Hansson  LZanchetti  ACarruthers  SG  et al.  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;3511755- 1762Article
51.
Tuomilehto  JRastenyte  DBirkenhager  WH  et al.  Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340677- 684Article
52.
Pahor  MKritchevsky  SBZuccala  GGuralnik  JM Diabetes and risk of adverse events with calcium antagonists. Diabetes Care. 1998;21193- 194
53.
Alderman  MHMadhavan  SCohen  H Calcium antagonists and cardiovascular events in patients with hypertension and diabetes. Lancet. 1998;351216- 217Article
54.
Hansson  LLindholm  LHNiskanen  L  et al.  Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet. 1999;353611- 616Article
55.
The Heart Outcomes Prevention Evaluation Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342145- 153Article
56.
ALLHAT Collaborative Research Group, Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;2831967- 1975Article
57.
World Health Organization–International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration, Protocol for prospective collaborative overviews of major randomized trials of blood-pressure lowering treatments. J Hypertens. 1998;16127- 137
58.
Joint National Committee, The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI). Arch Intern Med. 1997;1572413- 2446Article
59.
Koenig  WLowel  HLewis  MHormann  A Long-term survival after myocardial infarction: relationship with thrombolysis and discharge medication: results of the Augsburg Myocardial Infarction Follow-up Study, 1985 to 1993. Eur Heart J. 1996;171199- 1206Article
60.
Leitch  JWMcElduff  PDobson  AHeller  R Outcome with calcium channel antagonists after myocardial infarction: a community-based study. J Am Coll Cardiol. 1998;31111- 117Article
61.
Braun  SBoyko  VBehar  S  et al.  Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients. J Am Coll Cardiol. 1996;287- 11Article
62.
Gerstenblith  GOuyang  PAchuff  SC  et al.  Nifedipine in unstable angina: a double-blind, randomized trial. N Engl J Med. 1982;206885- 889Article
63.
Theroux  PTaeymans  YMorrisette  DBosch  XPelletier  GBWaters  DO A randomized study comparing propranolol and diltiazem in the treatment of unstable angina. J Am Coll Cardiol. 1985;5717- 722Article
64.
Andre-Fouet  XUsdin  JPGayet  C  et al.  Comparison of short-term efficacy of diltiazem and propranolol in unstable angina at rest: a randomized trial in 70 patients. Eur Heart J. 1983;4691- 698
65.
Muller  JEMorrison  JStone  PH  et al.  Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized double-blind, placebo-controlled comparison. Circulation. 1984;69740- 747Article
66.
Sirnes  PAOverskeid  KPedersen  TR  et al.  Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: the Norwegian Nifedipine Multicenter Trial. Circulation. 1984;70638- 644Article
67.
Branagan  JPWalsh  KKelly  PCollins  WCMcCafferty  DWalsh  MJ Effect of early treatment with nifedipine in suspected acute myocardial infarction. Eur Heart J. 1986;7859- 865
68.
Gibson  RSBoden  WETheroux  P  et al.  Diltiazem and reinfarction in patients with non–Q-wave myocardial infarction: results of a double-blind, randomized, multicenter trial. N Engl J Med. 1986;315423- 429Article
69.
Walker  LJEMacKenzie  GAdgey  AAJ Effect of nifedipine on enzymatically estimated infarct size in the early phase of acute myocardial infarction. Br Heart J. 1988;59403- 410Article
70.
Gottlieb  SOBecker  LCWeiss  JL  et al.  Nifedipine in acute myocardial infarction: an assessment of left ventricular function, infarct size, and infarct expansion. Br Heart J. 1988;59411- 418Article
71.
Danish Study Group on Verapamil in Myocardial Infarction, Verapamil in acute myocardial infarction. Eur Heart J. 1984;5516- 528
72.
The Israeli SPRINT Study Group, Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT): a randomized intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J. 1988;9354- 364
73.
Multicenter Diltiazem Postinfarction Trial Research Group, The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988;319385- 392Article
74.
Muller  JETuri  ZGPearle  DL  et al.  Nifedipine and conventional therapy for unstable angina pectoris: a randomized, double blind comparison. Circulation. 1984;69728- 739Article
75.
Wilcox  RGHampton  JRBanks  DC  et al.  Trial of early nifedipine in acute myocardial infarction: the Trent study. Br Med J (Clin res Ed). 1986;2931204- 1208Article
76.
Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group, Early treatment of unstable angina in the coronary care unit: a randomized, double-blind, placebo controlled comparison of recurrent ischemia in patients treated with nifedipine or metoprolol or both. Br Heart J. 1986;56400- 413Article
77.
Danish Study Group on Verapamil in Myocardial Infarction, Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II—DAVIT II). Am J Cardiol. 1990;66779- 785Article
78.
Goldcourt  UBehar  SReicher-Reiss  HZion  MMandelzweig  LKaplinsky  E Early administration of nifedipine in suspected acute myocardial infarction: the Secondary Prevention Reinfarction Israel Nifedipine Trial 2 Study. Arch Intern Med. 1993;153345- 353Article
79.
Held  PHYusuf  SFurberg  CD Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ. 1989;2991187- 1192Article
80.
The DEFIANT-II Research Group, Doppler flow and echocardiography in functional cardiac insufficiency: assessment of nisoldipine therapy. Eur Heart J. 1997;1831- 40
81.
Yusuf  SHeld  PFurberg  C Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish verapamil infarction trial (DAVIT-II) and other recent studies. Am J Cardiol. 1991;671295- 1297Article
82.
Yusuf  S Verapamil following uncomplicated myocardial infarction: promising, but not proven [editorial]. Am J Cardiol. 1996;77421- 422Article
83.
Ishikawa  KNakai  STakenaka  T  et al.  Short-acting nifedipine and dilitazem do not reduce the incidence of cardiac events in patients with healed myocardial infarction. Circulation. 1997;952368- 2373Article
84.
Hansen  JFHagerup  LSigurd  B  et al.  Cardiac event rates after acute myocardial infarction in patients treated with verapamil and trandolapril versus trandolapril alone. Am J Cardiol. 1997;79738- 741Article
85.
Theroux  PGregoire  JChin  CPelletier  GDe Guise  PJuneau  M Intravenous diltiazem in acute myocardial infarction: Diltiazem as Adjunctive Therapy to Activase (DATA) trial. J Am Coll Cardiol. 1998;32620- 628Article
86.
Boden  WEvan Gilst  WHScheldewaert  RG  et al.  Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomized placebo-controlled trial. Lancet. 2000;3551751- 1756Article
87.
Lichtlen  PRHugenholtz  PGRafflenbeul  WHecker  HJost  SDeckers  JW Retardation of angiographic progression of coronary artery disease by nifedipine: results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). Lancet. 1990;3351109- 1113Article
88.
Rengo  FCarbonin  PPahor  M  et al.  A controlled trial of verapamil in patients after acute myocardial infarction: results of the Calcium Antagonist Reinfarction Italian Study (CRIS). Am J Cardiol. 1996;77365- 369Article
89.
Peto  RCollins  RGray  R Large-scale randomized evidence: large, simple trials and overviews of trials. J Clin Epidemiol. 1995;4823- 40Article
90.
Berlin  JA The use of meta-analysis in pharmacoepidemiology. Strom  BLed.Pharmacoepidemiology 2nd ed. New York, NY John Wiley & Sons Inc1994;525- 547
91.
Gobel  EJAMHautvast  RWMvan Gilst  WH  et al.  Randomised, double-blind trial of intravenous diltiazem versus glyceryl trinitrate for unstable angina pectoris. Lancet. 1995;3461653- 1657Article
92.
Gobel  EJvan Gilst  WHde Kam  PJter Napel  MGMolhoek  GPLie  KI Long-term follow up after early intervention with intravenous diltiazem or intravenous nitroglycerin for unstable angina. Eur Heart J. 1998;191208- 1213Article
93.
Yusuf  SPeto  RLewis  JCollins  RSleight  P Beta-blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27335- 371Article
94.
Ryan  TJAnderson  JLAntman  EM  et al.  ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996;281328- 1428Article
95.
Not Available, Clinical Practice Guideline Number 10 (Amended): Unstable Angina: Diagnosis and Management.  Rockville, Md US Dept of Health and Human Services March1994;Publication 94-0602
96.
Scheidt  SLeWinter  MMHermanovich  JVenkataraman  KFreedman  D Efficacy and safety of nicardipine for chronic, stable angina pectoris: a multicenter randomized trial. Am J Cardiol. 1986;58715- 721Article
97.
Gheorghiade  MWeiner  DAChakko  SLessem  JNKlein  MD Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled randomized study. Eur Heart J. 1989;10695- 701
98.
Thadani  UZellne  SRGlasser  S  et al.  Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine: a new second-generation calcium channel blocker in angina pectoris. Circulation. 1991;842398- 2408Article
99.
Glasser  SPClark  PILipicky  RJHubbard  JMYusuf  S Exposing patients with chronic, stable exertional angina to placebo periods in drug trials. JAMA. 1991;2651550- 1554Article
100.
Pitt  BByington  RPFurberg  CD  et al.  Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;1021503- 1510Article
101.
Rehnqvist  NHemdahl  PBilling  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;1776- 81Article
102.
Fox  KMMulcahy  DFindlay  IFord  IDargie  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. Eur Heart J. 1996;1796- 103Article
103.
Heidenreich  PAMcDonald  KMHastie  T  et al.  Meta-analysis of trials comparing β-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;2811927- 1936Article
104.
Packer  M Calcium channel blockers in chronic heart failure: the risks of "physiologically rational" therapy. Circulation. 1990;822254- 2257Article
105.
Kostis  JBClifton  RLCosgrove  NMWilson  AC Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction. Am Heart J. 1997;133550- 557Article
106.
Packer  MO'Connor  CMGhali  JK  et al.  Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;3351107- 1114Article
107.
Cohn  JNZiesche  SSmith  R  et al.  Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril (V-HeFT III). Circulation. 1997;96856- 863Article
108.
Packer  MPRAISE-2 Investigators, Prospective Randomized Amlodipine Survival Evaluation 2.  Paper presented at: the 49th Scientific Sessions of the American College of Cardiology March 14, 2000 Anaheim, Calif
109.
Figulla  HRGietzen  FUwe  Z  et al.  Diltiazem improves cardiac function and exercise capacity in patients with idiopathic dilated cardiomyopathy: results of the Diltiazem in Dilated Cardiomyopathy Trial. Circulation. 1996;94346- 352Article
110.
Goldstein  REBoccuzzi  SJCruess  DNattel  S Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation. 1991;8352- 60Article
111.
Jick  HJick  SDerby  LEVasilakis  CMyers  MWMeier  CR Calcium-channel blockers and risk of cancer. Lancet. 1997;349525- 528Article
112.
Olsen  JHSorensen  HTSoren  F  et al.  Cancer risk in users of calcium channel blockers. Hypertension. 1997;291091- 1094Article
113.
Trenkwalder  PHendricks  PHense  HW Treatment with calcium antagonists does not increase the risk of fatal or non-fatal cancer in an elderly mid-European population: results from STEPHY II. J Hypertens. 1998;161113- 1116Article
114.
Vezina  RMLesko  SMRosenberg  LShapiro  S Calcium channel blocker use and the risk of prostate cancer. Am J Hypertens. 1998;111420- 1425Article
115.
Fitzpatrick  ALDaling  JRFurberg  CDKronmal  RAWeissfeld  JL Use of calcium channel blockers and breast carcinoma risk in postmenopausal women. Cancer. 1997;801438- 1447Article
116.
Hole  DJGillis  CRMcCallum  IR  et al.  Cancer risk of hypertensive patients taking calcium antagonists. J Hypertens. 1998;16119- 124Article
117.
Rosenberg  LRao  RSPalmer  JR  et al.  Calcium channel blockers and the risk of cancer. JAMA. 1998;2791000- 1004Article
118.
Michels  KBRosner  BAWalker  AM  et al.  Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the Nurses' Health Study. Cancer. 1998;832003- 2007Article
119.
Braun  SBoyko  VBehar  S  et al.  Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. J Am Coll Cardiol. 1998;31804- 808Article
120.
Jonas  MGoldbourt  UBokyo  VMandelzweig  LBehar  SReicher-Reiss  H Nifedipine and cancer mortality: ten-year follow-up of 2607 patients after acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12177- 181Article
121.
Sajadieh  AStorm  HHHansen  JFDAVIT Sudy Group, Verapamil and risk of cancer in patients with coronary artery disease. Am J Cardiol. 1999;831419- 1422Article
122.
Kanamasa  KKimura  AMiyataka  MTakenaka  TIshikawa  K Incidence of cancer in postmyocardial infarction patients treated with short-acting nifedipine and diltiazem. Cancer. 1999;851369- 1374Article
123.
Meier  RCDerby  LEJick  SSJick  H Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch Intern Med. 2000;160349- 353Article
124.
Cohen  HJPieper  CFHanlon  JTWall  WEBurchett  BMHavlik  RJ Calcium channel blockers and cancer. Am J Med. 2000;108210- 215Article
125.
Dong  EWConnelly  JEBorden  SP  et al.  A systematic review and meta-analysis of the incidence of cancer in randomized, controlled trials of verapamil. Pharmacotherapy. 1997;171210- 1219
126.
Messerli  FHGrossman  E Do calcium antagonists increase the risk for malignancies [editorial]? J Am Coll Cardiol. 1998;31809- 810Article
127.
Connor  JSawczuk  ISBenson  MC  et al.  Calcium channel antagonists delay regression of androgen-dependent tissues and suppress gene activity associated with cell death. Prostate. 1988;13119- 130Article
128.
Ray  SMKamendulis  LMGurule  MWYorkin  RDCorcoran  GB Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J. 1993;7453- 463
129.
Martin  SJGreen  DR Apoptosis and cancer: the failure of controls on cell death and cell survival. Crit Rev Oncol Hematol. 1995;18137- 153Article
130.
Heath  CWLally  CACalle  EEMcLaughlin  JKThun  MJ Hypertension, diuretics, and antihypertensive medications as possible risk factors for renal cell cancer. Am J Epidemiol. 1997;145607- 613Article
131.
Mason  RP Calcium channel blockers, apoptosis and cancer: is there a biologic relationship? J Am Coll Cardiol. 1999;341857- 1866Article
132.
Gore  JMSloan  MPrice  TR  et al.  Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study: Thrombolysis in Myocardial Infarction, Phase II, pilot and clinical trial. Circulation. 1991;83448- 459Article
133.
Hynynen  MKuitunen  ASalmenpera  M Surgical bleeding and calcium antagonists [letter]. BMJ. 1996;312313Article
134.
Pilotto  ALeandro  GFranceschi  MDi Mario  FValerio  G Antagonism to calcium antagonists [letter]. Lancet. 1996;3471761- 1762Article
135.
Grodecki-De Franco  PSteinhubl  STaylor  P  et al.  Calcium antagonist use and perioperative bleeding complications: an analysis of 5,157 patients [abstract]. Circulation. 1996;94 ((suppl)) I- 476
136.
Zuccala  GPahor  MLandi  F  et al.  Use of calcium antagonists and need for perioperative transfusion in older patients with hip fracture: observational study. BMJ. 1997;314643- 644Article
137.
Suissa  SBourgault  CBarkun  ASheehy  OErnst  P Antihypertensive drugs and the risk of gastrointestinal bleeding. Am J Med. 1998;105230- 235Article
138.
Smalley  WERay  WADaugherty  JRGriffin  MR No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease. Am J Epidemiol. 1998;148350- 354Article
139.
Rodriguez  LACCattaruzzi  CTroncon  MGAgostinis  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;15833- 39Article
140.
Kelly  JPLaszlo  AKaufman  DWSundstrom  AShapiro  S Major upper gastrointestinal bleeding and the use of calcium channel blockers [letter]. Lancet. 1999;353559Article
141.
Zuccala  GPedone  CCocchi  A  et al.  Use of calcium antagonists and hemoglobin loss in hospitalized elderly patients: a cohort study. Clin Pharmacol Ther. 2000;67314- 322Article
142.
Kaplan  RCHeckbert  SRKoepsell  TDRosendaal  FRPsaty  BM Use of calcium channel blockers and risk of hospitalized gastrointestinal bleeding. Arch Intern Med. 2000;1601849- 1855Article
143.
Kaste  MFogelholm  RErila  T  et al.  A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. Stroke. 1994;251348- 1353Article
144.
Mohr  JPOrgogozo  JMHarrison  MJG  et al.  Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cerebrovasc Dis. 1994;4197- 203Article
145.
Feigin  VLRinkel  GJEAlgra  AVermeulen  Mvan Gijn  J Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology. 1998;50876- 883Article
146.
Fallowfield  JMBlenkinsopp  JRaza  AFowkes  AGHiggins  TJCBridgman  KM Post-marketing surveillance of lisinopril in general practice in the UK. Br J Clin Pract. 1993;47296- 304
147.
Zucker  MLBudd  SEDollar  LEChernoff  SBAltman  R Effect of diltiazem and low-dose aspirin on platelet aggregation and ATP release induced by paired agonists. Thromb Haemost. 1993;70332- 335
148.
Hallas  J Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology. 1996;7478- 484Article
149.
Dunn  NRFreemantle  SNMann  RD Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression. Br J Clin Pharmacol. 1999;48230- 233Article
150.
Goodman  SHill  CBata  I  et al.  PROTECT (Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial): a randomized, double-blind clinical trial of diltiazem versus atenolol in secondary prophylaxis post non–Q-wave myocardial infarction. Can J Cardiol. 1996;121183- 1190
Review Article
May 14, 2001

Epidemiologic Review of the Calcium Channel Blocker DrugsAn Up-to-date Perspective on the Proposed Hazards

Author Affiliations

From the Department of Medicine and Cardiovascular Division, University of Pennsylvania Medical Center (Dr Kizer) and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine (Dr Kimmel), Philadelphia.

Arch Intern Med. 2001;161(9):1145-1158. doi:10.1001/archinte.161.9.1145
Abstract

In the setting of soaring popularity, postmarketing studies of calcium channel blockers came to suggest an increase in a variety of major adverse end points. The evidence, however, was largely observational, and large-scale trials capable of addressing the concerns were wanting. Clinical trials now support the safety and efficacy of the long-acting dihydropyridines for patients with both uncomplicated and diabetic hypertension, although conventional therapies and, in the latter case, angiotensin-converting enzyme inhibitors have superior proof of benefit. By contrast, short-acting dihydropyridines should be avoided. In the acute coronary syndromes, β-blockers remain the treatment of choice; the evidence for nondihydropyridines remains inconclusive. Stable angina calls for β-blockers as first-line therapy and nondihydropyridines as second-line therapy, whereas in ventricular dysfunction, safety data for nondihydropyridines are lacking. Initial reports of cancer, bleeding, and suicide have been contradicted by subsequent data, making the associations uncertain or unlikely. Remaining questions await completion of ongoing trials to better define the indications for these agents.

During the past several years, few issues in medical therapeutics have achieved more prominence than the debate over the safety and efficacy of calcium channel blockers (CCBs) in cardiovascular disease.19 This relates in no small part to the status of CCBs, in the early 1990s, as the most widely used class of agents for the treatment of hypertension in the United States.10 It is also a consequence of the wide variety of conditions to which these agents were applied after their introduction. The emergence of unfavorable observational data more than a decade after their first release forced the medical community to reassess the drugs' potential benefits and harms—only to find great uncertainty stemming from a paucity of reliable evidence. Purported deleterious effects of CCBs have ranged from increased cardiac events and mortality1114 to cancer,1517 major hemorrhage,1820 and suicide.21

Now, 5 years and numerous studies later, we have gained important insights, although uncertainty persists. Interpretation is complicated by the heterogeneous properties of different CCB classes and by the development of physiologically distinct long-acting preparations. While the subject has been reviewed lately,22,23 to our knowledge no recent work has approached the data from a detailed epidemiologic perspective. In this article, we review the literature reporting on the major outcomes above—selected from a systematic search of MEDLINE articles and their reference sections—paying particular attention to study methodology. Although not a formal meta-analysis, this review should guide us to epidemiology-based, up-to-date conclusions on the merits, shortcomings, and continuing unknowns of this important group of agents.

CCBs AND ADVERSE CORONARY EVENTS

The approval of CCBs in the 1980s rested on their proved efficacy on the surrogate outcomes of blood pressure lowering and angina relief.24 Few data on major cardiovascular outcomes or long-term safety were available. In this context, the appearance of 3 studies detailing adverse coronary events in 1995 produced grave concerns among the medical and lay communities alike.25 Psaty et al11 presented the results of a case-control study of hypertensive patients, demonstrating a 60% increase in the risk of myocardial infarction for CCBs compared with thiazide diurectics (TDs) or β-blockers (BBs).11 Soon after, Furberg and colleagues12,13 published a meta-analysis of coronary heart disease (CHD) trials documenting a significant association between high doses of nifedipine and increased overall mortality. To these reports, Pahor et al14 added their analyses of hypertensive subjects in the Established Populations for Epidemiologic Studies of the Elderly (EPESE) cohort, documenting higher mortality and coronary events for CCBs than for BBs. These reports generated an enduring controversy centered on the interpretation of observational studies to define suitable roles for these medications pending information from large-scale trials. This section will examine the totality of the evidence bearing on the association between CCBs and fatal and nonfatal coronary events.

HYPERTENSION
Observational Studies

Any assessment of Psaty and coworkers' and Pahor and colleagues' data must take into account the shortcomings intrinsic to observational studies evaluating medication effects. These studies present the special methodologic problem of "confounding by indication."26 In the observational design, treatment allocation is not under the control of the investigator, but at the discretion of the patient's physician. Since the physician's choice of the drug of interest depends on a host of distinguishing patient characteristics, exposed and unexposed subjects will be fundamentally different. When such differences in turn affect the outcome under evaluation, the requisite conditions for confounding will be satisfied. Investigators may apply standard techniques to adjust for these dissimilarities. These adjustments, however, are generally incomplete: the totality of clinical characteristics driving treatment selection is almost never fully measured and may, in fact, never be fully measurable.26,27 In consequence, attribution of an observed effect to the drug in question rather than to the clinical characteristics that prompted its use, especially when the risk estimate is modest, becomes problematic.2628

The odds ratios of myocardial infarction reported by Psaty et al were approximately 1.6, whereas Pahor and colleagues' nifedipine-associated relative risk of mortality was 1.7 (Table 1). In these observational settings, the modest magnitude of the estimates makes the reported associations suspect. Physicians responsible for the care of patients analyzed in these studies were at liberty to prescribe the antihypertensive agent of their choice. With regard to overall mortality in Pahor and coworkers' study, differential prescription of CCBs to patients with higher comorbidities would lead to confounding. Moreover, approved by the Food and Drug Administration for the treatment of stable angina pectoris, CCBs would tend to be used preferentially in this subset of patients at higher risk of myocardial infarction. This predilection for CCB use among patients with CHD was indeed observed by investigators in these studies. Although they adjusted for all measured confounders, such adjustments may not have entirely accounted for clinical differences tied to the selective use of CCBs that confer an increased risk of events.35 Last, while Pahor and associates' CHD risk estimates are high, their broad confidence intervals attest to their uncertainty.

Several observational studies failed to reproduce the findings in these original reports (Table 1), but these had few outcomes and often could not exclude large increases in risk (ie, 70% or greater).2931,33 Recognition of potential uncontrolled confounding led one subsequent study that did document an association to characterize its results as inconclusive.34 Thus, the true implication of the association remained unsettled. In addition, the Psaty et al and Pahor et al studies raised the question of whether their results, drawn from short-acting preparations, were applicable as well to the increasingly dominant long-acting CCBs. Unlike their short-acting counterparts, long-acting preparations do not cause the wide fluctuations in blood pressure or the same degree of neurohormonal activation—if any—believed to mediate the adverse effects.36 The case-control study by Alderman et al32 seemed to answer this question in the negative by documenting a 4-fold hazard for short-acting, but none for long-acting, preparations (Table 1). Yet, aside from the imprecision of some of these estimates, the study is prone to the same confounding-by-indication concerns that plague its peers. The prevalence of prior CHD was substantially higher in the short-acting than in the long-acting CCB group, which was in turn higher than in the alternative-drug group. These limitations make it impossible to draw firm conclusions from the findings.

Clinical Trials and Overviews

Early clinical trials of CCBs in hypertension were small and not specifically designed to assess major cardiovascular risks.37,38 In a meta-analysis of 98 published randomized trials of long-acting nifedipine, some 70% had enrolled 100 patients or less, and approximately two thirds had a follow-up of less than 13 weeks.39 The overview found no significant difference between monotherapy and active controls, but documented a significant reduction in cardiovascular events in the combination therapy comparison (Table 2). Nevertheless, lack of uniformity in the comparison arms limits interpretation of the results.

More evidence on dihydropyridines (DHPs) came in the form of larger trials from China,4042 but failure to blind investigators to drug assignment and alternate treatment allocation leaves these trials open to the influence of investigator bias in assigning active therapy to patients with better baseline health profiles. Nonetheless, these trials consistently showed reductions in stroke risk and, driven primarily by this end point, cardiovascular risk by DHPs (mostly long-acting) compared with placebo. None demonstrated differences in myocardial infarction events, but their confidence intervals were wide.

Data from the Systolic Hypertension in Europe (Syst-Eur) study,43 the largest double-blind, placebo-controlled randomized trial of CCBs in hypertension, provide confirmation of these findings. Investigators evaluated the DHP nitrendipine, with addition of enalapril maleate or hydrochlorothiazide as needed to achieve target blood pressure, in elderly patients with isolated systolic hypertension. The trial was stopped prematurely when a statistically significant 42% reduction in the primary end point of stroke was reached. Early termination, however, limited the power to detect differences in secondary end points, so that the trial was able to suggest, but not demonstrate, a reduction in myocardial infarction (Table 2). Subsequently, the Swedish Trial in Old Patients With Hypertension–2 (STOP-2)44 compared CCBs, angiotensin-converting enzyme inhibitors (ACEIs), and conventional therapy (BBs and/or TDs), supplemented by alternative treatment as necessary, and found no significant differences in the primary end point of cardiovascular mortality among these groups (Table 2). Nevertheless, the study did document higher CCB risks of myocardial infarction and congestive heart failure compared with the ACEI group.

Most recently, 2 additional randomized trials comparing CCBs with conventional therapies have reported their findings. The Nordic Diltiazem (NORDIL) Study45 compared short-acting diltiazem hydrochloride with TD/BB-based therapy in patients with mild hypertension, while the Intervention as a Goal in Hypertension Treatment study (INSIGHT)46 evaluated long-acting nifedipine vs TD-based therapy in hypertensive patients with 1 additional cardiovascular risk factor (Table 2). Neither trial demonstrated a difference in its primary end point of combined cardiovascular events. The NORDIL Study found a marginally significant diltiazem-associated reduction in stroke, but INSIGHT did not reproduce this finding for nifedipine. By contrast, the latter trial showed increases in fatal myocardial infarction and nonfatal heart failure not observed in the former.

Analysis of the results from these 4 large-scale trials requires consideration of several key points. First, a substantial proportion of patients in these trials withdrew from their assigned treatment (30%-40% in STOP-2 and INSIGHT). This is of significance for the active control trials, because it would tend to bias the drug comparisons in these negative studies toward the null hypothesis (ie, to dampen any true differences). Second, important numbers of patients were receiving more than 1 drug. In Syst-Eur and STOP-2, this was the case for more than 40%. Interpretation of Syst-Eur, then, must recognize that its benefits reflect a DHP-based regimen and not the exclusive effects of nitrendipine. For the active control trials, this would similarly blunt any differences between drug classes. The STOP-2, NORDIL, and INSIGHT figures likely overestimate the similarity between CCBs and the other drug groups. Third, the analysis of multiple outcomes, for instance, 48 separate end points in STOP-2, increases the likelihood that any given difference would arise merely by chance. Thus, the observed differences in secondary end points, especially when accompanied by broad confidence intervals, need to be viewed cautiously.

Insight into the validity of the STOP-2 differences, however, is provided by several trials evaluating CCBs and ACEIs in patients with diabetes mellitus. In addition to several post hoc subgroup analyses unfavorable to CCBs,47,52,53 2 clinical trials have shown increased cardiovascular events for CCBs compared with ACEIs in hypertensive diabetic populations. The Fosinopril vs Amlodipine Cardiovascular Events Randomized Trial (FACET)48 found the ACEI-associated risk to be half that of the DHP arm for the combined end point of myocardial infarction, stroke, and hospitalized angina. The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial,49 whose primary objective was to compare intensive to moderate blood pressure reduction strategies, was forced to terminate prematurely its arm of hypertensive subjects randomized to nisoldipine or enalapril on the secondary finding of a 5-fold–plus risk of myocardial infarction in the CCB group.

The results of ABCD and the FACET, however, cannot alone settle whether the differences in cardiac events stem from neutrality of CCBs and benefit of ACEIs, harm of CCBs and neutrality of ACEIs, or some combination thereof. Neither can the findings of STOP-2 in a population with a 10% prevalence of diabetes. But a number of additional trials shed light on this issue (Table 2). Hypertension Optimal Treatment (HOT)50 demonstrated a 67% decrease (95% confidence interval, 22%-86%) in major cardiovascular events in the diabetic subgroup randomized to the most intensive blood pressure reduction. To be sure, the absence of a felodipine-free control arm and the high concurrent use of ACEIs (41%) or BBs (28%) render impossible a conclusive claim of felodipine safety. Nevertheless, the analysis does attest to the superiority of intensive vs moderate felodipine-based regimens in diabetic patients, making important CCB hazards improbable. Moreover, post hoc analysis of the Syst-Eur diabetic subset documented significant reductions in all cardiovascular end points, and these reductions were substantially higher for diabetic patients than for nondiabetic patients.51

Further support for superior ACEI benefit comes from the recently reported Captopril Prevention Project (CAPPP)54 and Heart Outcomes Prevention Evaluation (HOPE) Study.55 While unable to demonstrate a difference in its primary cardiovascular end point among hypertensive patients randomized to captopril vs TD-BB, CAPPP documented significant ACEI-associated reductions in cardiac end points and mortality in its diabetic subgroup analyses. HOPE randomized patients with vascular disease or diabetes plus 1 additional cardiovascular risk factor to ramipril or placebo, demonstrating significant decreases in every major cardiovascular end point. In subgroup analyses, these findings held up irrespective of the presence of cardiovascular disease or diabetes mellitus. Thus, different event rates between diabetic patients receiving CCBs and ACEIs likely reflect ACEIs' superior cardioprotective properties and not CCB-mediated adverse effects.

In summary, based on clinical trials comparing long-acting DHPs with placebo, existing evidence supports the safety and efficacy of these agents in patients with mild to moderate hypertension. In populations at modest risk of CHD, such evidence is in the form of a reduction in cardiovascular events, driven primarily by a decrease in stroke. The data are insufficient to demonstrate a benefit for coronary events, as contrasted with existing data on TD-BB regimens. Large-scale trials evaluating long-acting DHPs or a short-acting non-DHP vs TDs, BBs, and/or ACEIs exclude moderate differences in combined cardiovascular events. Nevertheless, substantial treatment withdrawal and use of combination therapy across comparison groups may have biased the findings toward no difference. Moreover, significant differences in cause-specific outcomes, such as myocardial infarction, stroke, and heart failure, remain plausible. Data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)56 and from a projected meta-analysis of antihypertensive trials57 should help refine treatment selection. At present, continued adherence to the latest recommendation from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) of TDs and BBs as preferred, and long-acting DHPs and ACEIs as second-line, therapy for patients with uncomplicated hypertension (at modest risk of CHD) represents a sensible strategy58 (although the use of long-acting DHPs and diltiazem has received an important boost). Recent evidence, however, supports a different approach among diabetic hypertensive patients. In this population, regardless of the presence of proteinuria, strong consideration should be given to ACEIs as first-line therapy; TDs and long-acting DHPs are reasonable alternatives. Finally, short-acting DHPs have never demonstrated a reduction in cardiovascular outcomes in any group of patients with hypertension. Given their potential hazards, these agents should be avoided in the routine treatment of hypertension.

CORONARY ARTERY DISEASE–ACUTE CORONARY SYNDROMES
Observational Studies

In contrast to hypertension, data on CCBs in acute coronary syndromes have come primarily from clinical trials and overviews. In the time since the controversy, however, 2 long-term registries of patients surviving 28 days after myocardial infarction have supplied additional data.59,60 Both documented increases in coronary events and mortality when short-acting CCBs were compared with BBs, but when the comparison groups excluded patients receiving BBs, the differences in outcomes largely disappeared. A third large cohort study similarly showed no significant mortality difference in comparisons of patients with CHD on and off a regimen of short-acting CCBs.61 Taken together, these studies strengthen the notion of superior BB efficacy in secondary prevention but cannot settle CCB safety or efficacy questions in the absence of BB administration.

Clinical Trials and Overviews

Numerous randomized trials evaluated CCBs in acute coronary syndromes6278 well before the onset of the controversy. These assessed the effects of short-acting DHPs, primarily nifedipine, and non-DHPs, namely diltiazem and verapamil hydrochloride, on major CHD events compared with either placebo or BBs. In myocardial infarction, the drugs were assessed when instituted in the acute phase of the event, as well as with initiation thereafter and continuation long term. Yet, notwithstanding the observation of both favorable and unfavorable trends depending on the agent studied, no single trial could demonstrate a statistically significant effect on mortality or myocardial infarction outcomes—whether against placebo or BBs. This occurred despite the fact that, although most studies were insufficiently powered to detect moderate (20%) benefit (or harm), several were large enough to detect moderately large (30%-40%) effects in either direction.79 The lack of proof was summed up by an overview in 1989 by Held et al79 involving 19 100 patients that, moreover, found no evidence of heterogeneity among the different CCBs (Table 3).

Nonetheless, post hoc data review79 identified the possibility of benefit among non-DHPs, in contrast to a nonsignificant harmful effect for nifedipine. Furberg and coworkers' subsequent nifedipine meta-analysis12,13 included a single additional trial in patients with angiography-proven coronary disease.87 It documented a marginally significant overall association between nifedipine use and all-cause mortality, together with a significant data-derived dose-response relationship (Table 3). The pooled trials, however, were variously inhomogeneous, calling into question the validity of the findings. Furthermore, the overview left unaddressed the safety of the long-acting DHP preparations. The latter have since been evaluated by a single postinfarction trial that detected a nonsignificant effect involving very few outcomes.80

With respect to the non-DHPs, although individual placebo-controlled trials of diltiazem68,73 and verapamil71,77,88 in myocardial infarction yielded little evidence of cardiac benefit, exploratory analyses showed differential effects based on the presence or absence of congestive heart failure71,73 (Table 3). In these analyses, both diltiazem and verapamil reduced coronary events in patients without pulmonary congestion, and diltiazem appeared to increase their occurrence in patients with radiographic pulmonary edema. Subsequent overviews pooling the overall results of non-DHP trials documented nominally significant reductions in reinfarction (P<.05), but not mortality81,82 (Table 3). These findings, however, must be viewed with caution. Post hoc analyses increase detection of false-positive results,89 whereas cumulative meta-analyses are susceptible to the effects of statistical multiplicity81 and inclusion bias.90

More recent studies,8386,91,92 while providing additional evidence of non-DHPs' anti-ischemic properties, have failed to demonstrate benefits on myocardial infarction or mortality outcomes. Two small placebo-controlled trials did show benefit in composite end points that included ischemic symptoms—one, nonrandomized, of patients after infarction with stabilized heart failure receiving ACEIs,84 the other of thrombolytic-treated subjects with preserved left ventricular function.85 However, a moderate-sized randomized trial of diltiazem vs placebo after thrombolysis found no significant advantage to active therapy even when the combined primary end point included refractory ischemia.86 Thus, the reported differences by CCB class (non-DHP vs DHP) are without prospective confirmatory evidence of non-DHP benefits for major cardiovascular outcomes.

In conclusion, given the overwhelming evidence of BB benefit on coronary mortality when initiated early or late after myocardial infarction,93 and in accordance with the latest US guidelines,94 these agents remain the treatment of choice for this condition. Similarly, in line with evidence-based national recommendations,95 β-blockade constitutes first-line therapy in unstable angina. In both settings, the short-acting DHPs should be avoided. Scant data can be brought to bear on the long-acting DHPs. For the non-DHPs, there is no convincing proof of efficacy in the acute coronary syndromes for infarction or mortality outcomes, although the agents appear to afford benefits in symptom-driven end points. Some support does exist for the use of non-DHPs in patients with preserved left ventricular function when β-blockade is clearly contraindicated. The merits of this practice, however, require validation in the form of large-scale trials.

CORONARY ARTERY DISEASE–STABLE ANGINA

Long before the controversy, 3 small placebo-controlled DHP trials9698 in stable angina pectoris that found favorable effects on surrogate ischemic end points all reported more coronary events in the treatment arms, albeit too few to assess significance. Subsequently, an overview of 24 placebo-controlled trials accompanying new drug applications to the Food and Drug Administration found an increased rate of cardiovascular-related withdrawals in the CCB arms99 (Table 4). Lately, the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) documented an amlodipine-associated reduction in its composite end point, but this primarily reflected fewer procedures and recurrent anginal episodes (Table 4).100

Multiple trials have compared the efficacy of CCBs with BBs in symptom relief, but these also have had short follow-up and small numbers of cardiac events. The only 2 trials to have evaluated the long-term effects of CCBs vs BBs in stable angina, the Angina Prognosis Study in Stockholm (APSIS)101 and the Total Ischaemic Burden European Trial (TIBET),102 failed to show differences in major cardiovascular end points (Table 4). Because of their size, however, they cannot exclude large differences (47% in APSIS) in cardiac risk. The 2 studies account for most (100 of 116) of the cardiac events documented in a recently published meta-analysis.103 It is therefore not surprising that this overview did not detect differences in myocardial infarction and cardiac death (Table 4). Interestingly, it did find that discontinuation because of adverse events was lower for BBs. Regardless, because the stable angina data still allow moderate differences in risk, and in view of unproved differential symptom relief, β-blockade should be first-line (and long-acting calcium antagonism, second-line) therapy for this condition.

LEFT VENTRICULAR DYSFUNCTION

In patients with left ventricular dysfunction, CCBs' reflex sympathetic activation and negative inotropic effects have from early on raised concerns about their safety.104 Yet, while an exploratory analysis of CCB therapy in the Studies of Left Ventricular Dysfunction (SOLVD) showed an increase in myocardial infarction (Table 5),105 3 placebo-controlled trials of long-acting DHPs in patients receiving standard congestive heart failure therapy failed to demonstrate worse overall outcomes (Table 5).106108 Nonetheless, amlodipine-associated event reductions in patients with nonischemic cardiomyopathy, highlighted by post hoc analyses in the first Prospective Randomized Amlodipine Survival Evaluation (PRAISE),106 were not reproduced prospectively by the second Prospective Randomized Amlodipine Survival Evaluation (PRAISE-2).108 The PRAISE-2 results underscore the pitfalls of exploratory analyses, confirming long-acting DHPs' largely neutral effects among patients with treated heart failure, irrespective of cause.

For the non-DHPs, negative inotropic effects have been cited behind the post hoc differences in outcomes observed for subsets with impaired left ventricular function in myocardial infarction trials.73,77,110 Among patients receiving ACEI-based heart failure therapy, the nonrandomized trandolapril-verapamil study84 (Table 3) and the Diltiazem in Dilated Cardiomyopathy (DiDi) Trial109 provide some evidence of benefit. In the latter, randomization to diltiazem conferred significant improvements in left ventricular function and exercise capacity, although broad confidence bounds preclude conclusions on mortality (Table 5).109 In the aggregate, however, the lack of prospective or adequately powered data on CHD events for the non-DHPs, together with reports of increased heart failure,77,110 leaves their safety in left ventricular dysfunction very much in question.

LINKS TO CANCER

Early in the controversy's development, studies suggesting an increased risk of cancer1517 were also published (Table 6). The biological plausibility of the association was provided by reports that CCBs could interfere with calcium-mediated127129 Pahor and associates' findings,15,16 however, need to be viewed in the context of important limitations. In their analyses of the EPESE cohort, patients administered CCBs appeared to be sicker than their counterparts. Although the authors conducted adjustments for factors such as smoking, alcohol intake, and body mass index, these probably do not account for the full scope of clinical differences underlying differential cancer risk. Also, proved carcinogens generally exert selective tissue effects and are associated with latent periods beyond 4 years, the follow-up period in question.35 The absence of a latency period, together with the observation that the increased risk was not confined to a particular type of cancer, supports the notion that the elevated risk may have been the effect of residual confounding. Moreover, because ill patients are more prone to undergo workups that would uncover malignant neoplasms, the existence of potential detection bias in the analyses cannot be dismissed.

Despite 2 additional observational studies showing increased risks of colon17 and breast115 cancer, the preponderance of the ensuing clinical evidence has failed to substantiate an elevation in cancer risk, overall or site specific (Table 6).111114,116126 While a nested case-control study documented a nonsignificant increase in cancer risk among CCB vs BB users, it found no relationship between cancer and increasing treatment duration.111 Three-year follow-up of nearly 18 000 patients prescribed CCBs found no difference in observed (412) vs predicted (414) cancers based on national incidence rates.112 Retrospective analysis of a registry of hypertensive patients did not show a difference in incidence among CCB users, nonusers, and controls from 2 other populations.116 A case-control study that included 9513 cases and 6492 controls did not identify higher overall or site-specific risk for CCBs, with the exception of renal cell carcinoma, which was also found for BBs and ACEIs.117 Similarly, long-term follow-up in a large cohort study118 and in 2 randomized trials120,121 has failed to demonstrate an increased cancer incidence.

The observed association with renal cell carcinoma117 (Table 6) could reflect confounding by indication. This neoplasm has been found to be associated with hypertension, as well as with several other antihypertensive agents,117,130 suggesting that hypertension (and not the drugs used to treat it) may be the responsible factor. Alternatively, the association may represent reversal of cause and effect. Furthermore, a comprehensive review of the cellular and animal data regarding CCB-specific effects on apoptosis showed highly variable results, with the observation that effects in either direction required doses in the suprapharmacologic range.131 Thus, both biologically and epidemiologically, the evidence of a link to cancer is so far unpersuasive; studies with prospective collection of cancer incidence are needed before the issue can be settled conclusively.

LINKS TO MAJOR HEMORRHAGE

The possibility of a CCB-related hemorrhagic risk gained notice when a randomized trial in valvular surgery found an excess of major bleeding in the nimodipine arm compared with placebo (Table 7).18,19 Earlier, a post hoc analysis of the Thrombolysis in Myocardial Infarction (TIMI)–II trial had shown more intracerebral hemorrhage with CCBs,132 and postmarketing surveillance had found greater hemoglobin decreases for nifedipine relative to lisinopril.146 Concerns were heightened when Pahor and coworkers' EPESE analysis showed a greater risk of gastrointestinal hemorrhage for CCBs compared with BBs.20 The adverse effect was postulated to result from CCB-mediated inhibition of platelet aggregation and of protective vasoconstriction in response to hemorrhage.20,147 Since, additional reports have appeared demonstrating higher rates of in-hospital141 and post–hip surgery136 hemoglobin loss for patients taking CCBs. Moreover, in line with Pahor and associates' results, 2 subsequent observational studies have documented increased CCB risks of gastrointestinal hemorrhage.139,142

Nonetheless, much of the data on CCBs and bleeding is at odds with these findings. For gastrointestinal hemorrhage, 4 additional observational studies134,137,138,140 have failed to reproduce the Pahor et al results (Table 7). They also point up the shortcomings of the positive reports. β-Blockers, the reference category in both Pahor and coworkers' and Kaplan and associates'142 studies, have been suggested to protect against gastrointestinal bleeding,137 which could account for the higher CCB risk ratios observed therein. Misclassification of drug exposure, reflected in the Pahor et al study's implausibly low bleeding risk associated with nonsteroidal anti-inflammatory drugs,134,138,140 makes residual confounding by these agents in the sicker population prescribed CCBs difficult to discount. Similarly, in the Rodriguez et al study,139 failure of bleeding risk to decrease with time since discontinuation of CCBs may reflect uncontrolled confounding or bias. Further, it is significant that the Pahor et al study was prone to substantial misclassification of hospitalizations as resulting from gastrointestinal hemorrhage.138 This would have differentially affected the CCB-treated patients (higher comorbidities), artificially inflating the risk ratio for this outcome.140

Additional studies have not supported the CCB-bleeding association. In the case of perioperative bleeding in patients undergoing cardiac surgery, 2 studies133,135 failed to confirm the observations of the nimodipine trial for patients receiving various CCBs, one in a cohort of 5157 patients.135 Among patients with ischemic stroke or subarachnoid hemorrhage, another population at high risk of bleeding, randomized trials143 and meta-analyses144,145 have demonstrated CCB-related improvements in neurologic outcomes and no excess of bleeding or rebleeding. In coronary disease, a review of several major randomized trials (14 000 patient-years of follow-up)35 did not document any CCB-associated increase in bleeding, although data on this end point may not have been recorded systematically. In sum, the data bearing on a possible link between CCBs and bleeding are contradictory, although much of them speak against a materially increased risk. Definitive proof, however, can only come with prospective, systematic collection of data on this outcome in large-scale trials.56

CCBs AND SUICIDE

Two years after Hallas' prescription sequence symmetry analysis148 linked use of CCBs and ACEIs—but not BBs—to prescription of antidepressant medications, Lindberg and coworkers' Swedish cohort and cross-sectional ecologic studies21 found an association between CCBs and suicide not observed for other cardiovascular medications. Their work has significant limitations, however, including a small number of outcomes and limited adjustment for potential confounders. The latter is particularly important because BBs may be prescribed less frequently to patients with depression.

Subsequently, Bergman and colleagues (as reported by Kizer and Kimmel24) examined national Swedish pharmacy and forensic toxicology data to calculate medication-related rates of suicide in their country. They found figures of 0.01, 0.18, and 0.11 suicides per 1000 person-years for verapamil, diltiazem, and propranolol hydrochloride, respectively, which differ markedly from that reported by Lindberg et al (1.1 suicides per 1000 person-years) and are lower than the general suicide rate in Sweden (0.2/1000 person-years). Dunn and coworkers' recent cohort study149 using prescription-event monitoring similarly could not document an increased risk of depression for diltiazem or nicardipine relative to ACEIs. Thus, the proposed association between CCBs and suicide remains unconfirmed.

LIMITATIONS

The foregoing is not a formal meta-analysis, nor did we undertake to grade systematically the studies in question. Instead, the article represents our views after comprehensive review of the published literature. We attempted to present an unbiased summary of the available data based on study methodology. Nevertheless, the incompleteness of the data precludes definitive conclusions, and the controversial nature of the subject makes disagreement inevitable. Ultimate resolution of differences in opinion will have to await emergence of more robust evidence.

CONCLUSIONS

The characteristically limited data furnished by premarketing studies of CCBs, coupled with the absence of large-scale postmarketing trials, set the stage for alarm when observational studies reported a variety of serious hazards for what had become the most widely prescribed cardiovascular drugs worldwide. Nevertheless, some of the reported deleterious associations for this class of agents have not been borne out. Firmer evidence from large-scale trials has since appeared, principally for the less hemodynamically disruptive long-acting preparations. Together with improved knowledge of the clinical applications of other classes of antihypertensive–anti-ischemic agents, this allows for more informed therapy selection tailored to specific conditions.

In patients with uncomplicated hypertension at modest risk of CHD, long-acting DHPs and probably diltiazem seem safe and effective and remain reasonable alternatives after attempts with the first-line TDs and BBs (JNC-VI). Recent data, while buttressing safety contentions for CCBs in diabetic subgroups, support the superiority of ACEIs and compel extension of this therapy to patients with known cardiovascular disease. In accordance with national guidelines,58,94,95 BBs should continue to be first-line therapy for both acute coronary syndromes and stable angina, with ACEIs the mainstay of congestive heart failure management.

Many unknowns remain, such as the role of non-DHPs in patients with CHD intolerant of BBs or the relative merits (especially for cause-specific outcomes) of the various agents for hypertensive patients at modest CHD risk. In the latter, more data documenting coronary event reduction exist for TD-BBs than for long-acting DHPs, diltiazem, or ACEIs. In both cases, however, data from ongoing randomized trials and future meta-analyses should help to refine our therapeutic choices.56,150 Regardless, clinicians will have to continue to combine a critical assessment of the literature with sound clinical judgment to guide their decisions for the optimal welfare of these patients.

Back to top
Article Information

Accepted for publication November 7, 2000.

We thank Brian Strom, MD, MPH, for his helpful comments during the preparation of the manuscript.

Corresponding author: Stephen E. Kimmel, MD, MSc, University of Pennsylvania School of Medicine, 717 Blockley Hall, 423 Guardian Dr, Philadelphia, PA 19104-6021 (e-mail: skimmel@cceb.med.upenn.edu).

References
1.
Fagan  TC Calcium antagonists and mortality: another case of the need for clinical judgment [editorial]. Arch Intern Med. 1995;1552145Article
2.
Poole-Wilson  PA The calcium antagonist controversy: implications beyond drug prescription [editorial]. Eur Heart J. 1996;171131- 1133Article
3.
Kaplan  NM Do calcium antagonists cause death, gastrointestinal bleeding and cancer [editorial]? Am J Cardiol. 1996;78932- 933Article
4.
Not Available, Calcium-channel blockers: managing uncertainty [editorial]. Lancet. 1996;348487Article
5.
Dargie  HJFord  I Calcium-channel blockers and the clinician [editorial]. Lancet. 1996;348488- 489Article
6.
McMurray  JMurdoch  D Calcium-antagonist controversy: the long and short of it [editorial]? Lancet. 1997;349585- 586Article
7.
Califf  RMKramer  JM What have we learned from the calcium channel blocker controversy [editorial]? Circulation. 1998;971529- 1531Article
8.
Stanton  AV Calcium channel blockers: the jury is still out on whether they cause heart attacks and suicide [editorial]. BMJ. 1998;3161471- 1473Article
9.
Lubsen  J The calcium channel antagonist debate: recent developments. Eur Heart J. 1998;19 (Suppl I) I3- I7
10.
Manolio  TACutler  JAFurberg  CD  et al.  Trends in pharmacologic management of hypertension in the United States. Arch Intern Med. 1995;155829- 837Article
11.
Psaty  BMHeckbert  SRKoepsell  TD  et al.  The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274620- 625Article
12.
Furberg  CDPsaty  BMMeyer  JV Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;921326- 1331Article
13.
Furberg  CDPsaty  BM Corrections to the nifedipine meta-analysis. Circulation. 1996;931475- 1476
14.
Pahor  MGuralnik  JMCorti  MCFoley  DJCarbonin  PHavlik  RJ Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc. 1995;431191- 1197
15.
Pahor  MGuralnik  JMSalive  MECorti  MCCarbonin  PHavlik  RJ Do calcium-channel blockers increase the risk of cancer? Am J Hypertens. 1996;9695- 699Article
16.
Pahor  MGuralnik  JMFerrucci  L  et al.  Calcium-channel blockade and incidence of cancer in aged populations. Lancet. 1996;348493- 497Article
17.
Hardell  LFredrikson  MAxelson  O Case-control study in colon cancer regarding previous diseases and drug intake. Int J Oncol. 1995;8439- 445
18.
Wagenknecht  LEFurberg  CDHammon  JWLegault  CTroost  BT Surgical bleeding: unexpected effect of a calcium antagonist. BMJ. 1995;310776- 777Article
19.
Legault  CFurberg  CDWagenknecht  LE  et al.  Nimodipine neuroprotection in cardiac valve replacement: report of an early terminated trial. Stroke. 1996;27593- 598Article
20.
Pahor  MGuralnik  JMFurberg  CDCarbonin  PHavlik  RJ Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet. 1996;3471061- 1065Article
21.
Lindberg  GBingefors  KRanstam  JRastam  LMelander  A Use of calcium-channel blockers and risk of suicide: ecological findings confirmed in population-based cohort study. BMJ. 1998;316741- 745Article
22.
Freher  MChallapalli  SPinto  JVSchwartz  JBonow  ROGheorgiode  M Current status of calcium channel blockers in patients with cardiovascular disease. Curr Probl Cardiol. 1999;24236- 240Article
23.
Abernethy  DRSchwartz  JB Calcium antagonist drugs. N Engl J Med. 1999;3411447- 1457Article
24.
Kizer  JRKimmel  SE The calcium-channel blocker controversy: historical perspective and lessons for future pharmacotherapies: an International Society of Pharmacoepidemiology "Hot Topic." Pharmacoepidemiol Drug Saf. 2000;925- 36Article
25.
Lenfant  C The calcium channel blocker scare: lessons for the future [editorial]. Circulation. 1995;912855- 2856Article
26.
Strom  BLMelmon  KL The use of pharmacoepidemiology to study beneficial drug effects. Strom  BLed.Pharmacoepidemiology 2nd ed. New York, NY John Wiley & Sons Inc1994;449- 467
27.
Walker  AMStampfer  MJ Observational studies of drug safety [editorial]. Lancet. 1996;348489Article
28.
Taubes  G Epidemiology faces its limits. Science. 1995;269164- 169Article
29.
Aursnes  ILitleskare  IFroyland  HAbdelnoor  M Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Press. 1995;4157- 163Article
30.
Jick  HVasilakis  CDerby  LE Antihypertensive drugs and fatal myocardial infarction in persons with uncomplicated hypertension. Epidemiology. 1997;8446- 448Article
31.
Leader  SGMallick  RBriggs  NC Myocardial infarction in newly diagnosed hypertensive Medicaid patients free of coronary heart disease and treated with calcium channel blockers. Am J Med. 1997;102150- 157Article
32.
Alderman  MHCohen  HRoque  RMadhavan  S Effect of long-acting and short-acting calcium antagonists on cardiovascular outcomes in hypertensive patients. Lancet. 1997;349594- 598Article
33.
Abascal  VMLarson  MGEvans  JCBlohm  ATPoli  KLevy  D Calcium antagonists and mortality risk in men and women with hypertension in the Framingham heart study. Arch Intern Med. 1998;1581882- 1886Article
34.
Michels  KBRosner  BAManson  JE  et al.  Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women: the Nurses' Health Study. Circulation. 1998;971540- 1548Article
35.
Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension, Effects of calcium antagonists on the risks of coronary heart disease, cancer and bleeding. J Hypertens. 1997;15105- 115
36.
Grossman  EMesserli  FH Effect of calcium antagonists on plasma norepinephrine levels, heart rate and blood pressure. Am J Cardiol. 1997;801453- 1458Article
37.
The GLANT Study Group, A 12-month comparison of ACE-inhibitor and Ca-antagonist therapy in mild to moderate essential hypertension: the GLANT Study. Hypertens Res. 1995;18235- 244Article
38.
Borhani  NOMercuri  MBorhani  PA  et al.  Final outcome results of the multicenter isradipine diuretic atherosclerosis study. JAMA. 1996;276785- 791Article
39.
Stason  WBSchmid  CHNiedzwiecki  D  et al.  Safety of nifedipine in patients with hypertension: a meta-analysis. Hypertension. 1997;30 ((part 1)) 7- 14Article
40.
Cheng-Du Hypertension Intervention Collaborative Group, Randomised trial of treatment with nifedipine in hypertensive patients. Chin J Cardiol. 1994;22201- 205
41.
Gong  LZhang  WZhu  Y  et al.  Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens. 1996;141237- 1245Article
42.
Liu  LWang  JGGong  LLiu  GStaessen  JA Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens. 1998;161823- 1829Article
43.
Staessen  JAFagard  RLutgarde  T  et al.  Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350757- 764Article
44.
Hansson  LLindholm  LHEkbom  T  et al.  Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity: the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;3541751- 1756Article
45.
Hansson  LHedner  TLund-Johansen  P  et al.  Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study. Lancet. 2000;356359- 365Article
46.
Brown  MJPalmer  CRCastaigne  A  et al.  Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356366- 372Article
47.
Byington  RPCraven  TEFurberg  CDPahor  M Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events [letter]. Lancet. 1997;3501075- 1076Article
48.
Tatti  PPahor  MByington  RP  et al.  Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21597- 603Article
49.
Estacio  ROJeffers  BWHiatt  WRBiggerstaff  SLGifford  NSchner  RW The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non–insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338645- 652Article
50.
Hansson  LZanchetti  ACarruthers  SG  et al.  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;3511755- 1762Article
51.
Tuomilehto  JRastenyte  DBirkenhager  WH  et al.  Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340677- 684Article
52.
Pahor  MKritchevsky  SBZuccala  GGuralnik  JM Diabetes and risk of adverse events with calcium antagonists. Diabetes Care. 1998;21193- 194
53.
Alderman  MHMadhavan  SCohen  H Calcium antagonists and cardiovascular events in patients with hypertension and diabetes. Lancet. 1998;351216- 217Article
54.
Hansson  LLindholm  LHNiskanen  L  et al.  Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet. 1999;353611- 616Article
55.
The Heart Outcomes Prevention Evaluation Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342145- 153Article
56.
ALLHAT Collaborative Research Group, Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;2831967- 1975Article
57.
World Health Organization–International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration, Protocol for prospective collaborative overviews of major randomized trials of blood-pressure lowering treatments. J Hypertens. 1998;16127- 137
58.
Joint National Committee, The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI). Arch Intern Med. 1997;1572413- 2446Article
59.
Koenig  WLowel  HLewis  MHormann  A Long-term survival after myocardial infarction: relationship with thrombolysis and discharge medication: results of the Augsburg Myocardial Infarction Follow-up Study, 1985 to 1993. Eur Heart J. 1996;171199- 1206Article
60.
Leitch  JWMcElduff  PDobson  AHeller  R Outcome with calcium channel antagonists after myocardial infarction: a community-based study. J Am Coll Cardiol. 1998;31111- 117Article
61.
Braun  SBoyko  VBehar  S  et al.  Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients. J Am Coll Cardiol. 1996;287- 11Article
62.
Gerstenblith  GOuyang  PAchuff  SC  et al.  Nifedipine in unstable angina: a double-blind, randomized trial. N Engl J Med. 1982;206885- 889Article
63.
Theroux  PTaeymans  YMorrisette  DBosch  XPelletier  GBWaters  DO A randomized study comparing propranolol and diltiazem in the treatment of unstable angina. J Am Coll Cardiol. 1985;5717- 722Article
64.
Andre-Fouet  XUsdin  JPGayet  C  et al.  Comparison of short-term efficacy of diltiazem and propranolol in unstable angina at rest: a randomized trial in 70 patients. Eur Heart J. 1983;4691- 698
65.
Muller  JEMorrison  JStone  PH  et al.  Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized double-blind, placebo-controlled comparison. Circulation. 1984;69740- 747Article
66.
Sirnes  PAOverskeid  KPedersen  TR  et al.  Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: the Norwegian Nifedipine Multicenter Trial. Circulation. 1984;70638- 644Article
67.
Branagan  JPWalsh  KKelly  PCollins  WCMcCafferty  DWalsh  MJ Effect of early treatment with nifedipine in suspected acute myocardial infarction. Eur Heart J. 1986;7859- 865
68.
Gibson  RSBoden  WETheroux  P  et al.  Diltiazem and reinfarction in patients with non–Q-wave myocardial infarction: results of a double-blind, randomized, multicenter trial. N Engl J Med. 1986;315423- 429Article
69.
Walker  LJEMacKenzie  GAdgey  AAJ Effect of nifedipine on enzymatically estimated infarct size in the early phase of acute myocardial infarction. Br Heart J. 1988;59403- 410Article
70.
Gottlieb  SOBecker  LCWeiss  JL  et al.  Nifedipine in acute myocardial infarction: an assessment of left ventricular function, infarct size, and infarct expansion. Br Heart J. 1988;59411- 418Article
71.
Danish Study Group on Verapamil in Myocardial Infarction, Verapamil in acute myocardial infarction. Eur Heart J. 1984;5516- 528
72.
The Israeli SPRINT Study Group, Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT): a randomized intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J. 1988;9354- 364
73.
Multicenter Diltiazem Postinfarction Trial Research Group, The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988;319385- 392Article
74.
Muller  JETuri  ZGPearle  DL  et al.  Nifedipine and conventional therapy for unstable angina pectoris: a randomized, double blind comparison. Circulation. 1984;69728- 739Article
75.
Wilcox  RGHampton  JRBanks  DC  et al.  Trial of early nifedipine in acute myocardial infarction: the Trent study. Br Med J (Clin res Ed). 1986;2931204- 1208Article
76.
Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group, Early treatment of unstable angina in the coronary care unit: a randomized, double-blind, placebo controlled comparison of recurrent ischemia in patients treated with nifedipine or metoprolol or both. Br Heart J. 1986;56400- 413Article
77.
Danish Study Group on Verapamil in Myocardial Infarction, Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II—DAVIT II). Am J Cardiol. 1990;66779- 785Article
78.
Goldcourt  UBehar  SReicher-Reiss  HZion  MMandelzweig  LKaplinsky  E Early administration of nifedipine in suspected acute myocardial infarction: the Secondary Prevention Reinfarction Israel Nifedipine Trial 2 Study. Arch Intern Med. 1993;153345- 353Article
79.
Held  PHYusuf  SFurberg  CD Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ. 1989;2991187- 1192Article
80.
The DEFIANT-II Research Group, Doppler flow and echocardiography in functional cardiac insufficiency: assessment of nisoldipine therapy. Eur Heart J. 1997;1831- 40
81.
Yusuf  SHeld  PFurberg  C Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish verapamil infarction trial (DAVIT-II) and other recent studies. Am J Cardiol. 1991;671295- 1297Article
82.
Yusuf  S Verapamil following uncomplicated myocardial infarction: promising, but not proven [editorial]. Am J Cardiol. 1996;77421- 422Article
83.
Ishikawa  KNakai  STakenaka  T  et al.  Short-acting nifedipine and dilitazem do not reduce the incidence of cardiac events in patients with healed myocardial infarction. Circulation. 1997;952368- 2373Article
84.
Hansen  JFHagerup  LSigurd  B  et al.  Cardiac event rates after acute myocardial infarction in patients treated with verapamil and trandolapril versus trandolapril alone. Am J Cardiol. 1997;79738- 741Article
85.
Theroux  PGregoire  JChin  CPelletier  GDe Guise  PJuneau  M Intravenous diltiazem in acute myocardial infarction: Diltiazem as Adjunctive Therapy to Activase (DATA) trial. J Am Coll Cardiol. 1998;32620- 628Article
86.
Boden  WEvan Gilst  WHScheldewaert  RG  et al.  Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomized placebo-controlled trial. Lancet. 2000;3551751- 1756Article
87.
Lichtlen  PRHugenholtz  PGRafflenbeul  WHecker  HJost  SDeckers  JW Retardation of angiographic progression of coronary artery disease by nifedipine: results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). Lancet. 1990;3351109- 1113Article
88.
Rengo  FCarbonin  PPahor  M  et al.  A controlled trial of verapamil in patients after acute myocardial infarction: results of the Calcium Antagonist Reinfarction Italian Study (CRIS). Am J Cardiol. 1996;77365- 369Article
89.
Peto  RCollins  RGray  R Large-scale randomized evidence: large, simple trials and overviews of trials. J Clin Epidemiol. 1995;4823- 40Article
90.
Berlin  JA The use of meta-analysis in pharmacoepidemiology. Strom  BLed.Pharmacoepidemiology 2nd ed. New York, NY John Wiley & Sons Inc1994;525- 547
91.
Gobel  EJAMHautvast  RWMvan Gilst  WH  et al.  Randomised, double-blind trial of intravenous diltiazem versus glyceryl trinitrate for unstable angina pectoris. Lancet. 1995;3461653- 1657Article
92.
Gobel  EJvan Gilst  WHde Kam  PJter Napel  MGMolhoek  GPLie  KI Long-term follow up after early intervention with intravenous diltiazem or intravenous nitroglycerin for unstable angina. Eur Heart J. 1998;191208- 1213Article
93.
Yusuf  SPeto  RLewis  JCollins  RSleight  P Beta-blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27335- 371Article
94.
Ryan  TJAnderson  JLAntman  EM  et al.  ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996;281328- 1428Article
95.
Not Available, Clinical Practice Guideline Number 10 (Amended): Unstable Angina: Diagnosis and Management.  Rockville, Md US Dept of Health and Human Services March1994;Publication 94-0602
96.
Scheidt  SLeWinter  MMHermanovich  JVenkataraman  KFreedman  D Efficacy and safety of nicardipine for chronic, stable angina pectoris: a multicenter randomized trial. Am J Cardiol. 1986;58715- 721Article
97.
Gheorghiade  MWeiner  DAChakko  SLessem  JNKlein  MD Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled randomized study. Eur Heart J. 1989;10695- 701
98.
Thadani  UZellne  SRGlasser  S  et al.  Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine: a new second-generation calcium channel blocker in angina pectoris. Circulation. 1991;842398- 2408Article
99.
Glasser  SPClark  PILipicky  RJHubbard  JMYusuf  S Exposing patients with chronic, stable exertional angina to placebo periods in drug trials. JAMA. 1991;2651550- 1554Article
100.
Pitt  BByington  RPFurberg  CD  et al.  Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;1021503- 1510Article
101.
Rehnqvist  NHemdahl  PBilling  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;1776- 81Article
102.
Fox  KMMulcahy  DFindlay  IFord  IDargie  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. Eur Heart J. 1996;1796- 103Article
103.
Heidenreich  PAMcDonald  KMHastie  T  et al.  Meta-analysis of trials comparing β-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;2811927- 1936Article
104.
Packer  M Calcium channel blockers in chronic heart failure: the risks of "physiologically rational" therapy. Circulation. 1990;822254- 2257Article
105.
Kostis  JBClifton  RLCosgrove  NMWilson  AC Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction. Am Heart J. 1997;133550- 557Article
106.
Packer  MO'Connor  CMGhali  JK  et al.  Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;3351107- 1114Article
107.
Cohn  JNZiesche  SSmith  R  et al.  Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril (V-HeFT III). Circulation. 1997;96856- 863Article
108.
Packer  MPRAISE-2 Investigators, Prospective Randomized Amlodipine Survival Evaluation 2.  Paper presented at: the 49th Scientific Sessions of the American College of Cardiology March 14, 2000 Anaheim, Calif
109.
Figulla  HRGietzen  FUwe  Z  et al.  Diltiazem improves cardiac function and exercise capacity in patients with idiopathic dilated cardiomyopathy: results of the Diltiazem in Dilated Cardiomyopathy Trial. Circulation. 1996;94346- 352Article
110.
Goldstein  REBoccuzzi  SJCruess  DNattel  S Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation. 1991;8352- 60Article
111.
Jick  HJick  SDerby  LEVasilakis  CMyers  MWMeier  CR Calcium-channel blockers and risk of cancer. Lancet. 1997;349525- 528Article
112.
Olsen  JHSorensen  HTSoren  F  et al.  Cancer risk in users of calcium channel blockers. Hypertension. 1997;291091- 1094Article
113.
Trenkwalder  PHendricks  PHense  HW Treatment with calcium antagonists does not increase the risk of fatal or non-fatal cancer in an elderly mid-European population: results from STEPHY II. J Hypertens. 1998;161113- 1116Article
114.
Vezina  RMLesko  SMRosenberg  LShapiro  S Calcium channel blocker use and the risk of prostate cancer. Am J Hypertens. 1998;111420- 1425Article
115.
Fitzpatrick  ALDaling  JRFurberg  CDKronmal  RAWeissfeld  JL Use of calcium channel blockers and breast carcinoma risk in postmenopausal women. Cancer. 1997;801438- 1447Article
116.
Hole  DJGillis  CRMcCallum  IR  et al.  Cancer risk of hypertensive patients taking calcium antagonists. J Hypertens. 1998;16119- 124Article
117.
Rosenberg  LRao  RSPalmer  JR  et al.  Calcium channel blockers and the risk of cancer. JAMA. 1998;2791000- 1004Article
118.
Michels  KBRosner  BAWalker  AM  et al.  Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the Nurses' Health Study. Cancer. 1998;832003- 2007Article
119.
Braun  SBoyko  VBehar  S  et al.  Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. J Am Coll Cardiol. 1998;31804- 808Article
120.
Jonas  MGoldbourt  UBokyo  VMandelzweig  LBehar  SReicher-Reiss  H Nifedipine and cancer mortality: ten-year follow-up of 2607 patients after acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12177- 181Article
121.
Sajadieh  AStorm  HHHansen  JFDAVIT Sudy Group, Verapamil and risk of cancer in patients with coronary artery disease. Am J Cardiol. 1999;831419- 1422Article
122.
Kanamasa  KKimura  AMiyataka  MTakenaka  TIshikawa  K Incidence of cancer in postmyocardial infarction patients treated with short-acting nifedipine and diltiazem. Cancer. 1999;851369- 1374Article
123.
Meier  RCDerby  LEJick  SSJick  H Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch Intern Med. 2000;160349- 353Article
124.
Cohen  HJPieper  CFHanlon  JTWall  WEBurchett  BMHavlik  RJ Calcium channel blockers and cancer. Am J Med. 2000;108210- 215Article
125.
Dong  EWConnelly  JEBorden  SP  et al.  A systematic review and meta-analysis of the incidence of cancer in randomized, controlled trials of verapamil. Pharmacotherapy. 1997;171210- 1219
126.
Messerli  FHGrossman  E Do calcium antagonists increase the risk for malignancies [editorial]? J Am Coll Cardiol. 1998;31809- 810Article
127.
Connor  JSawczuk  ISBenson  MC  et al.  Calcium channel antagonists delay regression of androgen-dependent tissues and suppress gene activity associated with cell death. Prostate. 1988;13119- 130Article
128.
Ray  SMKamendulis  LMGurule  MWYorkin  RDCorcoran  GB Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J. 1993;7453- 463
129.
Martin  SJGreen  DR Apoptosis and cancer: the failure of controls on cell death and cell survival. Crit Rev Oncol Hematol. 1995;18137- 153Article
130.
Heath  CWLally  CACalle  EEMcLaughlin  JKThun  MJ Hypertension, diuretics, and antihypertensive medications as possible risk factors for renal cell cancer. Am J Epidemiol. 1997;145607- 613Article
131.
Mason  RP Calcium channel blockers, apoptosis and cancer: is there a biologic relationship? J Am Coll Cardiol. 1999;341857- 1866Article
132.
Gore  JMSloan  MPrice  TR  et al.  Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study: Thrombolysis in Myocardial Infarction, Phase II, pilot and clinical trial. Circulation. 1991;83448- 459Article
133.
Hynynen  MKuitunen  ASalmenpera  M Surgical bleeding and calcium antagonists [letter]. BMJ. 1996;312313Article
134.
Pilotto  ALeandro  GFranceschi  MDi Mario  FValerio  G Antagonism to calcium antagonists [letter]. Lancet. 1996;3471761- 1762Article
135.
Grodecki-De Franco  PSteinhubl  STaylor  P  et al.  Calcium antagonist use and perioperative bleeding complications: an analysis of 5,157 patients [abstract]. Circulation. 1996;94 ((suppl)) I- 476
136.
Zuccala  GPahor  MLandi  F  et al.  Use of calcium antagonists and need for perioperative transfusion in older patients with hip fracture: observational study. BMJ. 1997;314643- 644Article
137.
Suissa  SBourgault  CBarkun  ASheehy  OErnst  P Antihypertensive drugs and the risk of gastrointestinal bleeding. Am J Med. 1998;105230- 235Article
138.
Smalley  WERay  WADaugherty  JRGriffin  MR No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease. Am J Epidemiol. 1998;148350- 354Article
139.
Rodriguez  LACCattaruzzi  CTroncon  MGAgostinis  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;15833- 39Article
140.
Kelly  JPLaszlo  AKaufman  DWSundstrom  AShapiro  S Major upper gastrointestinal bleeding and the use of calcium channel blockers [letter]. Lancet. 1999;353559Article
141.
Zuccala  GPedone  CCocchi  A  et al.  Use of calcium antagonists and hemoglobin loss in hospitalized elderly patients: a cohort study. Clin Pharmacol Ther. 2000;67314- 322Article
142.
Kaplan  RCHeckbert  SRKoepsell  TDRosendaal  FRPsaty  BM Use of calcium channel blockers and risk of hospitalized gastrointestinal bleeding. Arch Intern Med. 2000;1601849- 1855Article
143.
Kaste  MFogelholm  RErila  T  et al.  A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. Stroke. 1994;251348- 1353Article
144.
Mohr  JPOrgogozo  JMHarrison  MJG  et al.  Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cerebrovasc Dis. 1994;4197- 203Article
145.
Feigin  VLRinkel  GJEAlgra  AVermeulen  Mvan Gijn  J Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology. 1998;50876- 883Article
146.
Fallowfield  JMBlenkinsopp  JRaza  AFowkes  AGHiggins  TJCBridgman  KM Post-marketing surveillance of lisinopril in general practice in the UK. Br J Clin Pract. 1993;47296- 304
147.
Zucker  MLBudd  SEDollar  LEChernoff  SBAltman  R Effect of diltiazem and low-dose aspirin on platelet aggregation and ATP release induced by paired agonists. Thromb Haemost. 1993;70332- 335
148.
Hallas  J Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology. 1996;7478- 484Article
149.
Dunn  NRFreemantle  SNMann  RD Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression. Br J Clin Pharmacol. 1999;48230- 233Article
150.
Goodman  SHill  CBata  I  et al.  PROTECT (Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial): a randomized, double-blind clinical trial of diltiazem versus atenolol in secondary prophylaxis post non–Q-wave myocardial infarction. Can J Cardiol. 1996;121183- 1190
×