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HEALTH TECHNOLOGY REVIEWThe Efficacy and Effectiveness of Sustained Release Oral Nitroglycerinin Comparison to Regular Delivery Isosorbide Dinitrate for theProphylactic Treatment of Stable Angina PectorisBCOHTA 94:1TB.C. Office of Health Technology AssessmentCentre for Health Services & Policy ResearchS·184· Koerner Pavilion· 2211 Wesbrook MallThe University of British ColumbiaVancouver, B.C. Canada V6T 1Z3K. Bassett, MD, PhDM. L. Rhone,BScSeptember 1994For more information about this document, or for additional copies:Tel.: (6Q4) 822-7049Fax: (604) 822-7975.BC Office of Health Technology AssessmentS184-Koerner Pavilion2211 Wesbrook MallThe University of British ColumbiaVancouver BC V6T lZ3Canada.ISBN: 1-896256-01-5.FOREWORDThe British Columbia Office of Health Technology Assessment (BCOHTA) was established on December 1,1990 by a grant to the University of British Columbia from the Province to promote and encourage the use ofassessment research in policy and planning activities at the government level and in policy, acquisition andutilization decisions at the clinical, operations and government levels. It is important to note that the role of theOffice is to appraise the scientific evidence only, without involvement in actual policy development for therequesting agency.Assessments are performed in response to requests from the public sector such as hospitals, physicians,professional associations, health regions, government; private sector groups such as manufacturers; andindividuals from the general public. One or more of the following criteria are used to determine the priority ofan assessment and the level of analysis: 1) number of users and potential change in quality of life; 2) acquisitionand operating costs to the health care system; 3) potential to influence provider and consumer behaviour as aresult of a review and 4) availability of accurate information and appropriate research skills.Electronic bibliographic databases and fugitive literature (that is not indexed or distributed publicly) are searchedusing predefined inclusion and exclusion criteria based on the specific search strategy. The critical appraisal ofthe retrieved evidence includes the formulation of logical and defensible conclusions about the technology understudy.Health Technology Assessment projects are conducted by BCOHTA faculty and staff who are expert insystematic review methodology. Reports are reviewed internally, and then sent to one or more experts from avariety of academic or clinical disciplines for external review. Comments and suggestions are considered priorto the production of a final document. Distribution of the reports is by request from the Office or throughinclusion on the BCOHTA mailing list; summary versions appear in the quarterly newsletter.The strength of the BCOHTA method of systematic review lies in the process of explicitly detailing themethodology and criteria used to produce recommendations which are based solely on the research evidence.This transparent and reproducible assessment process allows the reader to objectively review the evidence forthemselves. The ensuing reports are available for public distribution.Arminee Kazanjian, Dr. Soc.Chair, BCOHTA SteeringCommitteeCopies may be obtained from:B.C. Office of Health Technology AssessmentS 184 - Koerner Pavilion2211 Wesbrook MallVancouver. B.C.V6T 2B5 (604) 822-7049Kathryn D. Friesen. M.Sc.Program Manager, BCOHTAACKNOWLEDGEMENTSThe contributions of the following individuals are gratefully acknowledged:Internal review committee:Samuel B. Sheps, MD, MSc, FRCPCArminee Kazanjian, Dr. Soc.Kathryn D. Friesen, MScCarolyn J. Green, MScExternal Reviewers:Dr: Charles R. Kerr, MD, FRCPC, FACCDr. Morley Sutter, MD, PhDHead, Department of Health Care and EpidemiologyFaculty of MedicineThe University of British ColumbiaChair, BCOHTA Steering CommitteeAssociate Director, Centre for Health Services andPolicy ResearchAssociate Professor, Department of Health Care andEpidemiologyUniversity of British ColumbiaProgram Manager, BCOHTAUniversity of British ColumbiaResearch Associate, BCOHTAUniversity of British ColumbiaHead, Division of CardiologyDepartment of MedicineFaculty of MedicineUniversity of British ColumbiaProfessor, Department of Pharmacology andTherapeuticsFaculty of MedicineUniversity of British ColumbiaTABLE OF CONTENTSACKNOWLEDGEMENTS iFOREWORD iiTABLE OF CONTENTS iii1. BACKGROUND AND SIGNIFICANCE : 12. RESEARCH QUESTION 23. DEFINITIONS 24. TEClINOLOGY DESCRIP110N 35. DRUG COST AND UTILIZATION PATIERNS 46. APPRAISAL AND ANALYSIS OF RESEARCH REPORTINGPRIMARY DATA 66.1 Methodology 66.1.1 Search strategy 66.1.2 Inclusion criteria 76.2 Appraisal process 77. FINDINGS 87.1 Tolerance 97.2 Patient Compliance 107.3 Side effects 107.4 Drug interactions 107.5 Quality of life 108. DISCUSSION 119. CONCLUSION '" 11REFERENCES ~ 13BIBLIOGRAPHY 161. BACKGROUND AND SIGNIFICANCEThe British Columbia Pharmacare Program has recently reconsidered its policy of reimbursing eligiblepatients, primarily senior citizens, for the cost of all prescription and many non-prescription drugs. As aresult, the exclusive right of prescribing physicians to determine which drugs are suitable forreimbursement has been challenged. It is towards developing a more discriminating formulary that thispolicy is directed.Developing a more discriminating formulary requires not only a great deal of effort over an extendedperiod of time but also certain types of evidence. The evidence needed - termed relative efficacy - wouldbe from randomized controlled trials that compare drugs with one another. Relative efficacy studieshave not previously been required for drug licensing or distribution and, therefore, are less commonlyfound in the literature. Instead, the literature is dominated by the required absolute efficacy, or placebocontrolled studies. The paucity of relative efficacy evidence, especially for older drugs, leads todifficulties in the formulary review process as will be illustrated in this report.One of the concerns of the Drug Utilization Review Committee, which Pharmacare mandated to beginthe formulary review process, was the utilization pattern found for organic nitrates - drugs used for thetreatment of myocardial ischemic pain, termed angina pectoris. The Committee noted that despite thewide variety of products available for angina prophylaxis, approximately one half of the annualprovincial Pharmacare expenditure for this category of drugs - totaling 10.1 million dollars in 1993 * ­was spent on sustained release forms of oral nitroglycerin (SR-NG). This preparation costsapproximately ten times more per usual dose regimen than generic, regular release Isosorbide dinitrate(ISDN). They also noted that, in Saskatchewan and Ontario, SR-NG has never been listed inprovincially funded formularies, and in Manitoba, this product was recently delisted. The Committeetherefore asked whether scientific evidence supported the use of SR-NG oral tablets in comparison tocheaper oral tablet alternatives. While noting transdermal nitrates as additional alternatives to SR-NGwithin the nitrate category of drugs, the committee explicitly did not wish to examine the broaderquestion of transdermal nitrates at this time. In addition, the committee did not wish to consider othercategories of cardiac drugs also used for angina prophylaxis.• Includes the wholesale acquisition cost of drugs and dispensing fee (Source : Pharmacare Therapeutic Class Analys is 1993,B.C. Ministry of Health) .2. RESEARCH QUESTIONThe primary research question centers on whether any evidence, and if so what kind of evidence,supports use of SR-NG compared to regular release ISDN for the prophylactic treatment of stable anginapectoris". Other indications for oral nitrate use (ie. during cardiac procedures, in the acute post­myocardial infarction period) are not under examination. Also not examined are transdermally deliverednitrates, products also designed for angina prophylaxis.In the appropriate dosage··, all nitrates, including oral nitrates such as ISDN and SR-NG, are widelyaccepted as safe, effective anti-anginal agentsl -2• Our assessment, therefore, is focused on the evidenceconcerning relative rather than absolute efficacy and effectiveness of these two agents.Comparing ISDN and SR-NG is appropriate since reliable and valid clinical end-points exists for thiscategory of drugs both for efficacy, namely characteristic electrocardiographic changes and patientsymptom development during graded exercise testing3-S; and for effectiveness, using a quality of liferesearch tool designed for assessment of anti-anginal therapy6-7.3. DEFINITIONSOral means swallowed tablets, as opposed to tablets retained sublingually or buccally.Efficacy refers to patient benefit under ideal circumstances, such as correct dosage given to correctlydiagnosed patients and their responses measured both subjectively and objectively using valid andstandardized protocols.Effectiveness refers to patient benefit during less rigorous circumstances of daily life when the conditionunder examination is less carefully isolated in an experimental format and the treatment is less rigorouslyapplied. The measurements used to determine effectiveness vary from patient accounts to questionnairesto more rigorous comparisons with gold standard therapies.• Note: Sublingual and buccal tablets, as well as oral sprays are used in the treatment of acute angina as opposed to anginaprophylaxis. They are not considered in this review.•• See "Tolerance" section, 7.1.24. TECHNOLOGY DESCRIPTIONOral nitrates are long-standing drugs used both alone and in combination with other agents for patientswith ischemic heart disease. The advantages of these drugs include established efficacy, knownphysiological mechanism of action, minimal side effects, and relative low cost.The principle mechanism of action for oral nitrates are similar to all other nitrates. They act on themyocardium through preload* reduction by venodilatation, as well as dilating stenotic and nonstenoticcoronary arteries. Ischemia is thus prevented by both improving oxygen supply to the myocardium andreducing cardiac workload. The effect on preload is considered the predominant action by which nitratesrelieve angina. Nitrates also exert a smaller, less significant action in dilating arterioles thereby slightlyreducing afterload8**.ISDN and SR-NG, the two oral nitrates compared here, while differing in both chemical structure anddelivery form as well as initial metabolism, act through a common final physiological pathway. Thiscommon final mechanism justifies their comparison in this report.Isosorbide dinitrate, synthesized in 1938, remains as the world's most commonly used oral nitrate I. Inthe appropriate dosage, it is widely accepted as highly effective in the prophylaxis of myocardialischemic pain3,9. ISDN is marketed in various dosage strengths and is available in both regular releaseand sustained release forms.Oral SR-NG, similar to ISDN, was designed specifically for angina prophylaxis rather than for treatmentof an acute anginal episode. Unlike ISDN, however, because of its rapid absorption and metabolism,nitroglycerin must be delivered by an SR technology to provide angina prophylaxis (personalcommunication Rhone-Poulenc). This SR delivery is not currently manufactured as a generic analog.The limited number of studies to date provide poor evidence supporting sustained release efficacy'P'!'.* Preload refers to the pressure/volume status of the heart at the end of the pre-contraction phase of the cardiac cycle.** Afterload refers to the pressure/volume status of the heart during the contractile phase of the cardiac cycle .3Table 1. Administrative route, dosage and drug costs for oral prophylactic nitratetherapy In British ColumbiaDrug Usual dose range Cost/month-($)Oral tablets (Regular release)JSDNIsordll <l!) 10 ·30 mg BID· TID $ 9.20 - 16.20Coronex <l!)Genericdrugs (Novo-Sorblde<l!) 10 -30 mg BID - TID $ 7.46 - 9.99Apo-ISDN<l!)).Oral tablets (Sustained release)JSDNCedocard<l!) 20mg BID $28.69Coradur<l!) $27.78NitroglycerinNltrong-SR<l!) 2.6· 5.2 mg BID· TID $ 33.06 - 86.51~: Pharmacare TherapeuticClassAnalysis 1993,B.C.Ministry of Health... Cost! monthis basedon the wholesale acquisition cost as of December 1993and averageprovincial dispensing fee of $6.34.5. DRUG COST AND UTILIZATION PATTERNSTable 1 shows the dosage and drug costs of Pte various ISDN and SR-NG tablets prescribed in BritishColumbia. The four-year trend for B.C. Pharmacare utilization of each drug and delivery form areshown in Figures 1 and 2.ISDN cost ranges from approximately $0.02 to $0.05 for the highest strength generic regular releasetablets, to approximately $0.10 for similar dose regular release brand name tablets. Most commonly,regular release ISDN tablets are recommended in a three times daily schedule. ISDN is alsomanufactured in a rarely prescribed SR form. These sustained release tablets are usually prescribed twicedaily and are more expensive at $ 0.35/pill. In comparison, SR-NG is made in one strength which costsapproximately $ 0.44 per tablet and is generally used in a twice daily regiment/ (Table 1).4Figure 1. Volume (In millions) of regular and sustained release oral nitratetablets dispensed In British Columbia, 1990-199310.009.008.007.006.005.004.003.002.001.00O.OO~_L.--1990 1991 1992 1993• ISDN - SRo ISDN - RR• Nitroglycerin - SRFigure 2. Total expenditure (In millions) of regular and sustainedrelease oral nitrate tablets In British Columbia,~990-19934.54-jg 3.5.S] 3.S 2.5-~ 2.E:g 1.5ClI~~0 .501990 1991 1992 1993• ISDN · SRo ISDN - RR• Nitroglycerin· SR~:In 1993. Coronex ® 30 mg ISDN oral tablet not listed.In Figure 2. the wholesale acquisition cost and dispensing fees for the drugs were included in calculating totalexpenditure.~: Pharmacare Therapeutic Class Analysis 1990-1993. B.C. Ministry of Health.5Over the past four years, oral nitrate use in B.C. has moved steadily upwards towards long-acting forms(Figure 1). The market share for regular-release ISDN has declined 20%, while SR-NG has risen 50%(Figure 2). SR-ISDN, however, has shown little change representing less than 1% of the market share in1993. Since the average price per tablet for ISDN and SR-NG has risen only 5% during this period,increased utilization alone accounts for rising Pharmacare costs.6. APPRAISAL AND ANALYSIS OF RESEARCH REPORTINGPRIMARY DATA6.1 METHODOLOGYThe B.C. Office of Health Technology Assessment has developed standard protocols for the selectionand appraisal of primary data relevant to a particular research problem. Data are collected from bothuniversity library systems and associated electronic databases as well as the "fugitive literature".Fugitive literature includes material not published in peer-reviewed journals such as reports fromevaluative research groups, unpublished research, industry representatives, research and developmentorganizations, technical reports, consensus groups, .and technology assessment offices. Studies forreview are selected using inclusion criteria which are applied equally to all articles regardless of source.The critical appraisal process is then based on criteria for determining the extent to which the researchprotocol of the study under review conforms to scientific standards. This ensures that study findings arenot accepted unless supported by sound research methodology.6.1.1 Search strategyA number of electronic searches were conducted using the following databases: the National Library ofMedicine MEDLINE, HEALTH, HSTAR, EMBASE, Current Contents, Drug Information Fulltext,International Pharmaceutical Abstracts, Pharmaceutical News Index, Pharmacoprojects, andPharmaceutical and Healthcare Industry News Database. The search strategy spanned from 1966 toDecember 1993 and was limited to studies of human subjects. Key search terms used were"nitroglycerin", "isosorbide dinitrate", "angina pectoris", "drug administration routes", "delayed actionpreparations", "oral tablets", "effectiveness", and "efficacy".Information not indexed by electronic databases was sought from the pharmaceutical industry, researchand development agencies, and technology assessment organizations. In addition, information wassought directly from the pharmaceutical industry both through meetings with representatives Sept. 29,61993 and October 13th, 1993 at the University of British Columbia and through a written submissionreceived in the fall of 1993.6.1.2 Inclusion criteriaThe main criterion for inclusion in the critical appraisal process was that the study reported primary dataon the efficacy and/or effectiveness of ISDN or SR-NG. Background information regarding thepharmacological properties of alternate nitrate preparations, their therapeutic indications9•13 andhistorical developments of alternate drug delivery technology14 were also reviewed to provide a generalbackground to clinical and pharmacological issues.6.2 APPRAISAL PROCESSRetrieved reports were appraised using methodology based on the work of Chalmers et al lS and patternedafter Schechter and LeBlanc4, and Sackett", The standard criteria for assessing studies of therapeuticintervention and those specific to prophylactic anti-anginal therapies are listed in Table 2 and Table 3,respectively. Additional specific criteria, for example, the importance of a cross-over phase in studydesign, were derived from the scientific literature on nitrates, particularly the work of Silber! andElkayam'".Three categories of studies were identified:1. Ideal studies were randomized controlled trials comparing efficacy and effectiveness of oral ISDNandSR-NG.2. Less than ideal but also desirable were studies reporting primary data on ISDN and SR-NG relevantto a reference drug, such as isosorbide mononitrate (lSMN), in a comparable patient population.3. Minimally acceptable studies were those reporting absolute, that is drug/placebo, efficacy and/oreffectiveness studies on ISDN and SR-NG.71. The population inclusion and exclusion criteria are adequately described2. The assignment of patients to treatment is randomized3. Clinically important outcomes, including quality of life, are assessedobjectively and blindly4. The treatment is feasible to use in medical practice in the community5. There is at least 80% follow-up of subjects6. Both statistical and clinical significance is considered7. In the case of a study showing negative results, is power assessed?1. A placebo-control phase preceded the study2. The study included a cross-over design3. The study measured the time to onset of angina, documented with greaterthan 4mm ST segment depression on electrocardiogram, on a gradedexercise test4. The incidence and severity of angina pectoris was assessed duringnormal daily life5. Patient compliance to dosage schedule was measured or at least an attemptmade to count the pills used7. FINDINGSTwenty-three studies reporting primary data on nitrates were reviewed3,l D-14,17-33. However, because theresearch question focused on assessing relative drug efficacy and effectiveness, few studies were locatedthat provided data suitable for this review. In fact, no studies met the ideal inclusion criteria ofcomparing a clinical end point with oral ISDN and SR-NG using a single study population. Nor did anystudies meet the next to ideal criteria of comparing these two drugs to a reference drug in a comparablepatient population.8Seven studies reporting primary data on SR-NGIO.II and ISDN6.12,17.19.29 were considered minimallyacceptable and included in this review. They were appraised according to the criteria listed in Tables 2and 3. The results of the critical appraisal were examined in relation to five issues which were useful indiscriminating between these ISDN and SR-NG. These five issues: tolerance, compliance, side effects,drug interactions and quality of life are discussed below.7.1 ToleranceThe current debate and the central focus of current research regarding efficacy and effectiveness of oralnitrates for the prophylactic treatment of angina is whether the accepted initial benefit is sustained duringongoing use. Tolerance refers to the generally accepted observation that oral nitrates given in highenough doses for a sufficient length of time frequently produce diminishing and, in some patients, nobenefit when compared with placebo. This phenomenon may occur after a few days or up to a one weekperiod 16.19.29.Most evidence supports a nitrate free, or at least a nitrate low, period to sustain nitrate efficacy andeffectivenessl-Is The most widely accepted protocols involve daytime dosage with nighttime abstinence,termed an "eccentric" dosage schedule. How best to permit sub-therapeutic levels of nitrate to occurwhile maintaining efficacy and avoiding tolerance development remains controversial.No studies compared SR-NG and ISDN tolerance development in a single study population. One double­blind randomized study compared SR-NG with isosorbide mononitrate (ISMN), an oral nitratecommonly used in Europel l, It showed an absence of tolerance development to SR-NG using a threetimes daily dosage schedule in 12 patients over a 4 week period. These results are obviously suspectbecause of the small numbers involved, infrequent testing, and absent description of patient compliance.Furthermore, the results are difficult to generalize because of coincident use of a long acting beta­blocking agent. No other studies have suggested that the SR-NG is of particular benefit in avoidingtolerance development.Several longer and more rigorous, double blind, randomized, placebo-controlled, cross-over studies haveshown tolerance development with certain ISDN dosages and schedules, and not with others 1.29.33. Nosimilarly rigorous studies have examined SR-NG. Therefore, whether or not tolerance develops to thisSR-NG at any or all doses and dosage schedules remains essentially unknown.Thus current evidence is insufficient to distinguish between ISDN and SR-NG in terms of likelihood oftolerance development. However, both drugs seem equally suited for use in the eccentric dosingschedule, defined earlier.97.2 Patient CompliancePatient compliance means the degree to which patients take the prescribed amount of medication at thecorrect time intervals. High patient compliance, or close adherence to drug dosage and schedule, is anoften stated goal of drug therapy. Because SR-NG and ISDN differ in their daily dosage schedules, withSR-NG usually recommended twice versus ISDN three times daily, there is a theoretical likelihood thatpatients will comply more closely with the SR-NG schedule. Closer adherence to dosage schedule isseen as more likely with SR-NG because patients need only remember to take it twice, versus ISDNthree times per day. Although reasonable in theory, none of the studies reviewed in this report providedevidence to support this assumption. As well, this assumption may be erroneous because, unlike manyasymptomatic conditions such as hypertension, patients with ischemic heart disease have readilyrecognizable symptoms ranging from mild shortness of breath to angina pectoris and therefore thesepatients can readily assess their need for medication. Therefore, in the absence of myocardial ischemicpain, patients omitting a nitrate pill may be no worse off physically* and better off therapeutically dueto the decreased likelihood of tolerance development.7.3 Side effectsSide effects of oral nitrates, most commonly headaches and nausea, are almost always transient andconsidered mild 1. No research directly compared side effect profiles of ISDN versus SR-NG in a singlestudy population. Differences in side effect profiles, if they exist, seem unlikely to constitute asignificant factor differentiating between these two drugs.7.4 Drug interactionsNone of the studies attempted to examine SR-NG and ISDN in terms of actual or potential druginteractions either with cardiac or non-cardiac drugs.7.5 Quality of lifeDespite a valid and reliable quality of life research tool designed for assessment of anti-anginaltherapys-', no research was found which compared SR or other long acting with short acting nitratepreparations.* The current controversy regarding the clinical significance of what is termed "silent", that is painless, myocardialischemia, is noted. While potentially an important issue to oral nitrates as well as other prophylactic anginal agents,to date the literature provides no evidence considered of relevance to this discussion .108. DISCUSSIONBeyond the study design characteristics listed in Tables 2 and 3, several additional features arerecommended for research relevant to the formulary review process. These are listed in Table 4. Thefirst two characteristics, regarding the need for relative efficacy studies and a gold standard therapeuticagent reflect the gaps in the scientific literature as were illustrated by this report. The third, the need forquality of life assessments, reflects the growing general recognition that patient opinion on effectivenessshould play a greater role in determining allocation of scarce health care resources. The finalrecommendation reflects the need to have primary data on overall patterns of practice, including drugand other therapies, both before and after formulary decisions are made involving an individual drug.1. Relative drug efficacy and effectiveness must be measured in a randomlyallocated matched population2. A standard of therapy, or therapies, should be established within a class ofdrugs depending on clinical outcomes of interest·3. Studies should assess quality of life that includes an evaluation of patientopinion regarding drug effectiveness4. Studies should examine the overall impact of listing or delistlng a drug onthe thera eutlc ractlces of a cross section of h sicians over time8. CONCLUSIONSNo evidence was found to distinguish between ISDN and SR-NG in terms of efficacy, effectiveness,development of tolerance, patient compliance, significant side effect profile, drug interactions, orinfluence on quality of life. The most significant difference is the ten fold higher cost of SR-NG, versusgeneric ISDN, per usual dosage regimen.Given the increasing utilization of the SR-NG form, and the documented increased costs, this lack ofevidence of any significant benefit suggests consideration should be given to the development ofguidelines for the appropriate use of the different forms of nitroglycerine provided through the provincialformulary ."11The drug utilization and formulary review process places an increased burden on drug manufacturers todemonstrate relatiye as well as absolute efficacy of their products. This is particularly important when adrug is considerably more expensive than an established alternative. In future, lack of proof of positivebenefit may be sufficient to not list a drug on, or consider withdrawing it from, a formulary paymentscheme.12REFERENCES1 Silber S. Nitrates: why and how should they be used today? Current status of the clinical usefulness ofnitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate. Eur J Clin Pharmacol 1990;38(1 Suppl):S35-S51.2Abrams J. A symposium: nitroglycerin therapy - a contemporary perspective. Am J Cardiol1987;60(15): IH-3H.3 Kattus AA. Treadmill exercise protocols to demonstrate effectiveness of nitrate drugs in relief of anginapectoris: duration of action and degree of functional enhancement. Cardiology 1981;68(2 Suppl):161­168.4 Schechter M, LeBlanc FE. Critical appraisal of published literature. In: Hanstroidle W, Spitzer 0,McPeek B, Mulder ns, and McKneally MF, editors. Principles and practice of research: strategies forsurgical investigators. New York: Springer-Verlag, 1986:i 12-117.5 Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinicalmedicine. 2nd ed. U.S.A.: Little, Brown and Co.,1985:359-78.6 Nissinen A Wiklund I, Lahti T, Akkila J, Wilson A, Wahl M et al. Anti-anginal therapy and quality oflife: a comparison of the effects of transdermal nitroglycerin and long-acting oral nitrates. J ClinEpidemioI1991;44(9):989-97.7 Wilson A, Wiklund I, Lahti T, Wahl M. A summary index for the assessment of quality of life inangina pectoris. J Clin EpidemioI1991;44(9):981-88.8 Fung HL. Pharmacokinetics and pharmacodynamics of organic nitrates. Am J CardioI1987;60:4H-9H.9 Elkayam U, Aronow WS. Glyceryl trinitrate (nitroglycerin) ointment and isosorbide dinitrate: a reviewof their pharmacological properties and therapeutic use . Drugs 1982;23:165-94.10 Winsor T, Berger HI. Oral nitroglycerin as a prophylactic anti-anginal drug: clinical, physiologic, andstatistical evidence of efficacy based on a three-phase experimental design. Am Heart J 1975;90(5):611­26.1311 Arvill A, Jorgensen E, Anggard E. Nitrate tolerance measured by exercise tests: a comparison betweenisosorbide-5-mononitrate and sustained-release nitroglycerin. Lakartidningen 1991;88(21): 1962-68.12 Rao YV, Reddy KS, Wasir HS. Assessment of anti-anginal efficacy of long-acting sustained releaseisosorbide dinitrate in comparison with short-acting isosorbide dinitrate. Indian Heart J 1991:43(2):97­100.13 Parker JO. Controlled release isosorbide-5-mononitrate in angina pectoris: a comparison with standardformulation isosorbide dinitrate. Can J CardioI1991;7(3):125-30.14 Thadani U, Fung lIL, Darke A, Parker JO. Oral isosorbide dinitrate in angina pectoris: comparison ofduration of action and dose-response relation during acute and sustained therapy. Am J Cardiol 1982;49:411-19.15 Chalmers TC, Smith H, Blackburn B et al. A method for assessing the quality of a randomized controltrial. Controlled Clin Trials 1981;2:31-49.16 Elkayam U. Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies forprevention. Ann Intern Med 1991;114:667-77.17 Kattus AA, Alvaro AB, Coulson A. Effectiveness of isosorbide dinitrate and nitroglycerin in relievingangina pectoris during uninterrupted exercise. Chest 1975;67(6):640-46.18Zohman LR, Carroll LR. The nitroglycerin exercise test. Cardiology 1981;68(2 Suppl):169-77.19 James MA, Papouchado M, Jones N. Attenuation of nitrate effect during an intermittent treatmentregimen and the time course of nitrate tolerance. Eur Heart J 1991;12:1266-72.20 Schneider W, BuBmann WO, Kober G, Kaltenback M. Long term effect of organic nitrates in anginapectoris on drug formulation and the mode of testing. Z. Kardiol 1989;78(2 Suppl):83-87.21 Kattus AA, Alvaro AB, Zohman LR, Coulson AH. Comparison of placebo, nitroglycerin andisosorbide dinitrate for effectiveness of relief of angina and duration of action. Chest 1979;75(1):17-23.22 Hirschleifer I. Peripheral hemodynamic effects of oral controlled-release nitroglycerin (Nitrong) inman. Current Ther Res 1973;15(4):159-64.1423 Cole SL, Kiaye H, Berger NJ. Anti-anginal effect of oral controlled-release nitroglycerin (Nitrong) inpatients with coronary artery disease: double-blind, randomized, multiple, cross-over study. Amer FedClin Res 1975;23:177A.24 Blinder S. The evaluation of controlled release nitroglycerin tablets (Nitrong) in the treatment ofangina pectoris. Current Ther Res 1965 (Dec);7(12):769-72.25 Bassan MM, Rogel S. A comparison of the day-long anti-anginal effectiveness of nitrolgycerin patcheswith that of three times daily isosorbide dinitrate: a double-blind study using dose titration. Eur Heart J1992;13:1265-70.26 Gumbleton M, Benet 12. Pharmacological activity of the dinitrate metabolites of nitroglycerinfollowing their oral administration to healthy volunteers. Br J Clin PharmacoI1991;31:211-213.27 Winsor T, Kaye H, Mills B. Hemodynamic response of oral long-acting nitrates: evidence ofgastrointestinal absorption. 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