Reasons for overprescription of mononitrates: the paradigm of stable angina pectoris treatment

Abstract

Background

Oral nitrates, beta-blockers, and calcium channel blockers are used to treat stable angina pectoris (SAP). The 2 therapeutic subtypes of oral nitrates are mononitrates and dinitrates, with no evidence that 1 subtype is more efficacious than the other. Although practice guidelines in Great Britain and Israel recommend dinitrates as the first-line drug for SAP, in practice, many physicians in those 2 countries prescribe mononitrates.

Objective

The aim of this study was to identify factors that influence specialist physicians (family practitioners, internists, and cardiologists) in Israel when prescribing nitrates for the prevention of SAP symptoms.

Methods

A group of specialists was given a self-administered questionnaire regarding their treatment of choice for a patient with SAP described in a hypothetical case vignette. End points for prescribing preferences were evidence-based information, cost, and the influence of pharmaceutical company representatives.

Results

One hundred ten specialists were given the questionnaire. Eighty-nine specialists (45 men, 44 women; mean age, 50.4 years; range, 34–67 years; response rate, 80.9%) completed it (39 family practitioners, 29 internists, and 21 cardiologists). Seventy-eight respondents (87.6%) chose to prescribe nitrates for the case vignette, and among those, 54 (69.2%) chose mononitrates and 24 (30.8%) chose dinitrates (P = 0.034). The choice of mononitrates over dinitrates was mainly affected by habit (25/54 [46.3%]) and the belief that mononitrates are more effective, safer, and/or less expensive than dinitrates (21/54 [38.9%]). Drug costs for the patient significantly influenced more family practitioners than hospital specialists (P<0.05).

Conclusions

In contrast to guideline recommendations, the paradigm of SAP treatment with nitrates in this study was characterized by significantly more prescriptions for mononitrates than dinitrates. This situation contributes to the erosion of the scarce resources of the health care system in Israel. Further efforts are needed to increase physicians' awareness of quality, cost, and choices when prescribing drugs.

Introduction

More than 6 million people in the United States have angina, and an estimated 550,000 new cases of angina are diagnosed each year, among them 400,000 cases of stable angina pectoris (SAP). SAP is a clinical syndrome caused by myocardial ischemia.¹ Oral nitrates, beta-blockers, and calcium channel blockers are suggested for the treatment of SAP.^2–4 The aim of this study was to identify factors that influence specialist physicians (family practitioners, internists, and cardiologists) in Israel when prescribing nitrates for the prevention of SAP symptoms.^5,6

The 2 therapeutic subtypes of oral nitrates are mononitrates and dinitrates, with no evidence that 1 subtype is more efficacious than the other. In Israel, isosorbide dinitrate has been used for >70 years and 5-mononitrate, the active metabolite of isosorbide dinitrate, has been used for >20 years. Both are taken sublingually, are available in standard and slow-release formulations, and have been proved effective in relieving SAP symptoms for up to 12 hours.^7–9 A once-daily regimen, rather than multiple daily doses, is recommended to improve compliance,¹⁰ prevent tolerance,¹¹ and improve quality of life.¹²

Physicians have been shown to choose between the 2 subtypes of nitrates based on clinical status, compliance, cost-effectiveness, and patients’ convenience.¹² Dinitrates are the recommended first-line drug for SAP in Great Britain¹³ and Israel.¹⁴ Physicians are expected to follow these recommendations and to prescribe dinitrates more often than mononitrates. However, in a previous study,¹⁵ we found that 88% of physicians prescribed mononitrates in practice, whereas only 5% prescribed a combination of dinitrates and mononitrates that enhances the development of tolerance to nitrates.^11,16 A total of 12% prescribed dinitrate monotherapy.

Among the noteworthy reasons given by physicians for lack of adherence to clinical practice guidelines are a lack of awareness of, familiarity with, or agreement with the guidelines^17,18; inertia of a previous habit¹⁷; enthusiasm for using new drugs¹⁹; and the strong influence of pharmaceutical company representatives.²⁰

The reasoning for overprescribing mononitrates is puzzling. Because of our previous findings¹⁵ that physicians prescribe more mononitrates than dinitrates for SAP, we conducted a survey to identify factors influencing different specialist physicians (family practitioners, internists, and cardiologists) in Israel toward this preference.

Subjects and methods

This cross-sectional descriptive study was conducted in the southern region of Israel (the Negev) from 2001 to 2002. This area includes 750,000 inhabitants enrolled in 1 of 4 health maintenance organizations (HMOs) operating in the country. The 2 study sites are the only 2 hospitals in the region, Soroka University Medical Center (Beer-Sheva) and Barzilai Medical Center (Ashkelon); both are affiliated with the Faculty of Health Sciences at Ben-Gurion University of the Negev (Beer-Sheva).

The study population comprised board-certified specialists (family practitioners, internists, and cardiologists) practicing in the Negev. This group included all internists and cardiologists working at either of the hospitals and all family practitioners working in the community setting of the HMOs. Resident physicians, non–board-certified physicians, and physicians who validated the questionnaire used in this study were excluded.

The dependent variables included prescription preference (mononitrates vs dinitrates); knowledge regarding drug efficacy, safety, and cost; the influence of pharmaceutical company representatives; and awareness of clinical practice guidelines. The independent variables included physician age, sex, specialty, and workplace.

The specialists were requested to answer 12 multiple-choice questions on a self-administered questionnaire (Appendix). The questionnaire included a hypothetical case vignette of a hypertensive patient treated with beta-blockers who presents to the physician's office describing symptoms of SAP. Two board-certified cardiologists and 1 specialist in health care management developed the case vignette, which was later internally validated by 10 board-certified specialists (6 internists, 2 cardiologists, and 2 family practitioners) who were excluded from the study. Hospital specialists (internists and cardiologists) were approached by 1 of the researchers during routine activity hours or during staff meetings in coordination with the head of the department. Family practitioners were handed questionnaires during a weekly postgraduate gathering and weekly meetings in coordination with the head of the program and the clinic managers. The questionnaires were collected as soon as they were completed.

On the questionnaire, specialists were first asked to choose a preferred drug to treat SAP from a list of drugs that included mononitrates and dinitrates. Specialists who chose mononitrates or dinitrates then were asked to describe the factors that influenced their choice. Specialists who indicated that the efficacy and safety profile of mononitrates and dinitrates are similar and that they chose a drug out of habit were asked to specify the source of the habit. In addition, all specialists were asked specifically whether information regarding cost for the patient and cost for the HMO influenced their choice of treatment. They also were asked about whether they received guidelines from their employers as to the treatment of SAP, factors that influence their decisions to choose nitrates in practice, whether they tended to consult someone when prescribing nitrates, and whom they would consult if necessary. Questions regarding the specialists' demographic characteristics appeared at the end of the questionnaire.

Statistical analysis

Chi-square tests were performed to assess differences in prescribing patterns between physicians according to their specialties and hospital affiliation. Statistical significance was set at P<0.05.

Results

The study population comprised 110 specialists (45 family practitioners, 39 internists, and 26 cardiologists). The response rates, by specialty and by affiliation, are shown in Table I. Eighty-nine specialists (80.9%) completed the questionnaire (39/45 family practitioners [86.7%], 29/39 internists [74.4%], and 21/26 cardiologists [80.8%]). The respondents comprised 45 men and 44 women (mean age, 50.4 years; range, 34–67 years); the mean (SD) time since board certification was 10.1 years (range, 1–33 years). Among hospital specialists (50/89 [56.2%]), 32 (64.0%) were from Soroka University Medical Center and 18 (36.0%) were from Barzilai Medical Center.

Table I.

Response rates (no. [%]) among physicians given the study questionnaire.

		Hospital Specialists
Specialty	Respondents	Soroka University Medical Center (n = 43)	Barzilai Medical Center (n = 22)
Family practitioners (n = 45)	39 (86.7)	–	–
Hospital specialists
Internists (n = 39)	29 (74.4)	17/24 (70.8)	12/15 (80.0)
Cardiologists (n = 26)	21 (80.8)	15/19 (78.9)	6/7 (85.7)
Total (N = 110)	89 (80.9)	32 (74.4)	18 (81.8)

Seventy-eight of the 89 specialists (87.6%) who completed the questionnaire chose drugs from the nitrate group (39 family practitioners [50.0%], 26 internists [33.3%], and 13 cardiologists [16.7%]) (Figure). Among these, 54 (69.2%) chose to prescribe mononitrates and 24 (30.8%) chose dinitrates (P = 0.034). No statistically significant difference was found between the rate of dinitrate prescription when comparing family practitioners and hospital specialists.

Figure.

Nitrate prescription patterns among specialists who chose to prescribe them (n = 78). P = 0.034 for mononitrates versus dinitrates (all specialties).

The specialists were asked about following the treatment guidelines (a formulary) they received from their employers (HMOs or hospitals). Twenty-nine (32.6%) were unaware of such guidelines. Of the 60 (67.4%) who were aware of the guidelines' existence, only 47 (78.3%) indicated that they had received a formulary. Of these, 26 (55.3%) chose to prescribe mononitrates and 21 (44.7%) dinitrates (P = NS). Of the 42 specialists (47.2%) who indicated that they had not received a formulary, 36 (85.7%) chose mononitrates and 6 (14.3%) dinitrates (P = 0.031).

Table II compares the prescription rates of mononitrates and dinitrates between hospital specialists. Thirty-nine of 50 (78.0%) hospital specialists chose to prescribe nitrates. One of 9 cardiologists (11.1%) and 7 of 15 internists (46.7%) from Soroka University Medical Center chose dinitrates. None of the specialists at Barzilai Medical Center chose dinitrates (P = 0.04).

Table II.

Prescription patterns for mononitrates and dinitrates among hospital specialists who responded to the questionnaire (n = 50), by medical center.

		No. (%) Prescribing Nitrates
Hospital Setting	Ratio Who Did Versus Did Not Prescribe Nitrates	Mononitrates (n = 31)	Dinitrates (n = 8)
Soroka University
Medical Center
Internists	15:2	8 (53.3)	7 (46.7)
Cardiologists	9:6	8 (88.9)∗	1 (11.1)
Barzilai Medical
Center
Internists	11:1	11 (100.0)∗	0 (0.0)
Cardiologists	4:2	4 (100.0)∗	0 (0.0)
Total	39:11	31 (79.5)	8 (20.5)

^∗P<0.04 versus dinitrates.

The factors influencing respondents (n = 89) to choose a nitrate drug are shown in Table III. Among all specialties, the most common factor influencing this choice was previously successful personal experience (80 [89.9%]). Drug cost for the HMO was found to have only a minor influence on specialists (26 [29.2%]). Cost for the patient influenced the prescription patterns of family practitioners significantly more than hospital specialists (P<0.05).

Table III.

Factors (no. [%]) influencing respondents (n = 89) to choose a nitrate drug, by specialty.^∗

		Hospital Specialists
Factor	Family Practitioners (n = 39)	Internists (n = 29)	Cardiologists (n = 21)
Previous good experience with the drug	36 (92.3)	26 (89.7)	18 (85.7)
Evidence based	33 (84.6)	27 (93.1)	16 (76.2)
Cost of drug for the patient	26 (66.7)†	16 (55.2)	7 (33.3)
Article in professional literature	24 (61.5)	20 (69.0)	12 (57.1)
Cost of drug for HMO	15 (38.5)	7 (24.1)	4 (19.0)
HMO recommendations	14 (35.9)	6 (20.7)	5 (23.8)
Professional conference	7 (17.9)	11 (37.9)	5 (23.8)
Colleague's successful experience	6 (15.4)	10 (34.5)	6 (28.6)
Marketing efforts by pharmaceutical company representative	6 (15.4)	8 (27.6)	6 (28.6)

HMO = health maintenance organization.

^∗All respondents, including those who chose not to prescribe nitrates for the case vignette (n=11), were instructed to answer this question. Respondents were to choose ≥4 factors. Not all cardiologists chose ≥4 factors.

^†P<0.05 versus hospital specialists.

Of the 54 respondents (60.7%) who preferred mononitrates to dinitrates, 25 (46.3%) indicated that they prescribe mononitrates out of habit and 4 (7.4%) because it is routine practice in their department. Twenty-one respondents (38.9%) believed that mononitrates are more efficient, safer, and/or less expensive than dinitrates (Table IV). The only statistically significant between-group difference in the reason for choosing mononitrates was habit; 12 of 23 family practitioners (52.2%) chose mononitrates for that reason compared with 13 of 31 hospital specialists (41.9%) (8/19 internists [42.1%] and 5/12 cardiologists [41.7%]) (P<0.05).

Table IV.

Reasons (no. [%]) for prescribing mononitrates over dinitrates, by specialty.

		Hospital Specialists
Reason	Family Practitioners (n = 23)∗	Internists (n = 19)	Cardiologists (n = 12)	Total (N = 54)∗
Out of habit	12 (52.2)†	8 (42.1)	5 (41.7)	25 (46.3)
Safer	6 (26.1)	0 (0.0)	1 (8.3)	7 (13.0)
More efficacious	3 (13.0)	7 (36.8)	3 (25.0)	13 (24.1)
Less expensive	1 (4.3)	0 (0.0)	0 (0.0)	1 (1.9)
Routine practice in department	0 (0.0)	3 (15.8)	1 (8.3)	4 (7.4)
Patients request this medicine	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
No answer given	1 (4.3)	1 (5.3)	2 (16.7)	4 (7.4)

^∗Percentages do not add to 100% due to rounding.

^†P<0.05 versus hospital specialists.

Seventy-eight specialists (87.6%) responded to the question regarding their awareness of drug cost when prescribing nitrates. Of these, 57 (73.1%) claimed to be aware of the higher cost of mononitrates compared with dinitrates; however, 39 of these (68.4%) indicated that they prescribe mononitrates. A similar prescribing pattern was found among the 21 specialists (26.9%) who claimed not to be aware of drug cost; among these, 12 (57.1%) indicated that they prescribe mononitrates.

Discussion

In the past century, 2 subtypes of oral nitrates were developed for the treatment of SAP: mononitrates (newer and more expensive) and dinitrates (older and less expensive). Mononitrates are markedly overused,^15,21 despite policymakers' recommendations,¹³ even though the efficacy and tolerability of the newer subtype has not been documented to be better than that of dinitrates. This situation helps erode the limited resources of the health care system in Israel.

In our study, significantly more specialists prescribed mononitrates than dinitrates in the hypothetical case vignette and in practice. Furthermore, significantly more specialists who received a formulary prescribed mononitrates than dinitrates. In contrast, awareness or unawareness of drug cost did not change the pattern of prescribing mononitrates. One study²⁰ showed that general practitioners and specialists from different fields have different reasons for prescribing new drugs for treatment of angina, as well as for hypertension and depression; hospital specialists in that study used more evidence-based medicine to inform their decisions.

Compared with cardiologists and internists, more family practitioners are used to prescribing mononitrates (habit) and because they were more sensitive to drug costs for the patients. However, habit and sensitivity to drug costs are insufficient to engender major change in prescription habits with regard to low-cost drugs.^19,22

We did not find other differences between family practitioners and hospital specialists as to the factors influencing them to prefer prescribing mononitrates. These findings may be related to the fact that consulting physicians are highly regarded by general practitioners, so that a general practitioner would not change a specialist's prescription, even if the consultant prescribed a drug not recommended in the guidelines.^19,20

Almost all physicians in our study prescribe mononitrates out of habit and because they wrongly believe that mononitrates are more efficient, safer, and/or less expensive than dinitrates. These findings contrast with the fact that most physicians claim in our study to choose nitrate drugs based on medical evidence as provided in articles in the professional literature, attendance at professional conferences, and awareness of guideline recommendations. Further studies are needed to explain these contradictions.¹⁵

Significantly more physicians from Soroka University Medical Center prescribed dinitrates compared with physicians from Barzilai Medical Center (P = 0.04). This difference may be due to the fact that some physicians at Soroka University Medical Center recommended that the HMO formulary favor mononitrates. They were involved in many discussions and lectures within the hospital, enabling them to remind their colleagues about the recommendation.

Marketing efforts by pharmaceutical companies are so intense that they directly influence physicians' prescription patterns.²⁰ In fact, only 1 physician in our study admitted to being convinced by drug company representatives to favor and prescribe mononitrates. In the case of nitrates, it is economically worthwhile to market mononitrates and not dinitrates. Although mononitrates are not more efficacious than dinitrates, marketing efforts may influence perceptions in favor of prescribing mononitrates. Family practitioners tend to try prescribing new samples they have received from drug representatives, and they rely less on scientific facts than the information provided by specialized consultants.²⁰ Once family practitioners have prescribed a new drug, they tend to continue using it.²⁰

In Israel and other countries, such as Great Britain, dinitrates are less expensive than mononitrates at a ratio of 1:2–3.¹⁵ Changing a physician's prescribing patterns from an existing drug is challenging, is cost effective, and justifies interference of the academic detailing sort,^23–25 an effective method in which the representatives of health care providers train a group of physicians using lectures similar to those given by pharmaceutical company representatives. The only difference is the goal of the lecture, which is to promote the use of the drugs designated by the HMO due to their cost-effectiveness compared with alternative drugs. Studies have shown that building the system and training the staff cause significant changes in drug prescription patterns and result in substantial cost savings.²⁶

Clinical guidelines have become a popular way of influencing physicians' behavior,²⁷ guiding physicians through evidence-based information to a consensus of an optimal treatment strategy among specialists. However, many reports have described difficulties in physicians' assimilating clinical guidelines^17,25,28 and in changing physicians' performance, as a result of a lack of qualitative studies and evidence to convince the physicians to adhere to the clinical guidelines.^26,29 Guidelines used in conjunction with medical education or reminder systems do improve physician management of several chronic conditions and may improve clinical outcomes.^30–32 In addition, performance feedback to physicians has been shown to have a small but positive effect on medical practice.^30,33

In some cases, it is not financially worthwhile to change inappropriate prescription patterns.²¹ In Israel, dinitrates are included among services covered by the health care system (they are almost free). However, they are recommended by only 1 HMO as the preferred drug for the treatment of SAP, and no other efforts have been made to implement the guidelines and positively influence the physicians to prescribe dinitrates. In addition to distributing guidelines, educational efforts aimed at the prescription of dinitrates for new patients with SAP may forestall the need to change an existing prescription, which is difficult to do.^19,20 Incentives created by decision makers (policymakers, healthcare–system managers) will change physicians' prescribing habits. However, studies of cost-effectiveness are needed to define the type, magnitude, and effect of these efforts.

Conclusions

Nitrate treatment for patients with SAP is characterized by significantly more specialists prescribing mononitrates than dinitrates. Family practitioners and hospital specialists in the Negev prescribe mononitrates out of habit and because they wrongly believe that mononitrates are more efficient, safer, and/or less expensive than dinitrates. This situation contributes to the erosion of the scarce resources of the health care system in Israel.

Further studies are needed to understand this phenomenon and to find efficient methods of increasing physicians' awareness of quality, costs, and alternatives when prescribing new drugs.

APPENDIX. Questionnaire

Please read the following hypothetical case vignette and then answer the following questions.

David, a 70-year-old male, suffers from hypertension that is balanced by beta-blockers. He comes to your office complaining of pressing chest pain. The pain lasts about five minutes, and is resolved with rest. The incidents of pain are brought on by moderate physical effort, and first appeared three months prior to his visit to your office.

• 1.
  Which of the following will be your first choice of treatment for David:

  • a.
    Isosorbide dinitrate (Isotard)
  • b.
    Isosorbide mononitrate (twice daily—Mononit, Monocord)
  • c.
    Isosorbide mononitrate (once daily—Mononit Retard)
  • d.
    Changing the beta-blocker dosage
  • e.
    A calcium channel blocker
  • f.
    An angiotensin-converting enzyme (ACE) inhibitor
  • g.
    A combination of the above: —
  • h.
    Other: —

  • If your answer to question 1 was from the mononitrate group (b or c), please answer the following:

    • A.
      Why did you prefer this group to the dinitrate group of drugs?

      • 1.1.1.
        Mononitrates are more efficacious than dinitrates
      • 1.1.2.
        Mononitrates are safer than dinitrates
      • 1.1.3.
        Mononitrates are cheaper than dinitrates
      • 1.1.4.
        The efficacy and safety profile of the drugs are similar; I'm used to prescribing this medicine (habit)
      • 1.1.5.
        It is routine practice in my department
      • 1.1.6.
        Patients request this medicine
  • If your answer to question 1 was from the dinitrate group (a), please answer the following:

    • B.
      Why did you prefer this group to the mononitrate group of drugs?

      • 1.2.1.
        Dinitrates are more efficient than mononitrates
      • 1.2.2.
        Dinitrates are safer than mononitrates
      • 1.2.3.
        Dinitrates are cheaper than mononitrates
      • 1.2.4.
        The efficacy and safety profile of the drugs are similar; I'm used to prescribing this medicine (habit)
      • 1.2.5.
        It is routine practice in my department
      • 1.2.6.
        Patients request this medicine
  • If your answer to question A or B is “the drugs are similar” (4), please answer the following:

    • C.
      What is the source of the habit?

      • 1.3.1.
        My colleagues prescribe this medicine
      • 1.3.2.
        The head of my department instructs the doctors to prescribe this medicine
      • 1.3.3.
        In medical conferences I've heard of a technological advantage to this medicine which is: —
      • 1.3.4.
        I've been convinced by a pharmaceutical representative that this medicine has technological advantages over others
      • 1.3.5.
        I'm relying on evidence-based medicine
      • 1.3.6.
        My clinical experience with this drug
      • 1.3.7.
        A combination of answers: —
• 2.
  Choose four or more topics you consider when prescribing medication to a patient:

  • —Frequency of ingestion
  • —Side effects
  • —Dosages
  • —Interactions with other drugs
  • —Dietary habits
  • —Alternative preparations
  • —Other: —
• 3.
  Rate the following drugs by their cost for the patient (to your knowledge), with 1 being the lowest cost and 3 the highest:

  • —Isosorbide dinitrate (Isotard)
  • —Isosorbide mononitrate (twice daily—Mononit, Monocord)
  • —Isosorbide mononitrate (once daily—Mononit Retard)
• 4.
  Is the cost of the drug for the patient a factor in your decision to choose it?

  • Yes/No
• 5.
  Is the cost of the drug for the HMO a factor in your decision to choose it?

  • Yes/No
• 6.
  Have you received guidelines from the HMO in which you are working about the type of drug you should use for treating angina pectoris?

  • Yes/No
  • If yes, state how:

    • a.
      Lecture
    • b.
      Personal approach
    • c.
      Formulary
    • d.
      Other
• 7.
  Mark four or more factors that influence your decision when choosing a drug from the nitrate group.

  • —Previous good experience with the drug
  • —Previous good experience of a colleague with the drug
  • —An article you recently read in the professional international literature
  • —Recommendations of the HMO
  • —Cost of the drug for the patient
  • —Cost of the drug for the HMO
  • —Marketing efforts by pharmaceutical company representative (eg, conference, lecture)
  • —Professional conference on the issue
  • —Adjusting a drug to the patient following evidence-based medicine
• 8.
  Do you usually consult other doctors about prescribing nitrates?

  • a.
    Always
  • b.
    Usually
  • c.
    Sometimes
  • d.
    Seldom
  • e.
    Never
• 9.
  If needed, whom would you consult?

  • a.
    An internist
  • b.
    A family physician
  • c.
    A cardiologist

  • Demographic Data
  • Year of birth 19—
  • Gender M/F
  • Specialty

    • 9.4.1.
      Cardiology
    • 9.4.2.
      Internal medicine
    • 9.4.3.
      Family
  • Year of certification: —
  • Residency in Israel Yes/No
  • Community practice only Yes/No
  • Hospital practice only Yes/No
  • Combined practice (community and hospital) Yes/No
  • Which HMO do you work for?

    • 9.10.1.
      Clalit Health Care Services
    • 9.10.2.
      Maccabi Health Care Services
    • 9.10.3.
      Leumit Health Care Services
    • 9.10.4.
      Meuchedet Health Care Services