FORUM--LETTERS TO THE EDITOR

THROMBOLYTICS AND MARITIME MEDICAL CARE

To the Editor: Vacationing on large cruise ships is a popular pastime among

Americans and Europeans. Cruising is a $5.5 billion business that contributes $1.2 to $1.5 billion annually to the U.S. economy in di- rect purchase of goods and supplies. More than 4 million people board these ships during the course of a year. These vessels accommodate a wealth of needs, with exercise rooms, jogging courses, casinos, discos, first-run movie theaters, an innumerable array of organized activities, and other entertainment. Cruise ves- sels are like small cities on the water. However, although exercise and activities attract the interest of some passengers, others enjoy the sedentary satisfactions of the extraordinary catering facilities. These vacationers are often elderly and have a tendency to exceed their normal exercise levels. They often drink alcohol and eat to excess because availability is essentially unlimited and price inclusive.

Some cruise companies request health-screening profiles to be completed on registration. Many vacationers, however, choose not to fill out the questionnaires, preferring to take their chances. The ships have infirmary-like medical clinics that can accommodate many day-to-day medical problems. The facilities vary widely, with some capable of cardiac monitoring and assisted ventilation. High-risk or seriously ill patients are transported to onshore hos- pitals if helicopters, air ambulances, or Coast Guard boats are available. Helicopters hover above these vessels and a basket is lowered for patient pickup. If a cruise ship is crossing the Pacific or Atlantic oceans, this wait for assistance can be as much as 2 days. Other times the ship's course is rerouted to get help for the pas- senger. Maritime law does not require that medical care be provided on these ships, but low-level care is provided by most of the larger companies.

Depending on the ship's country of origin, a non-English- speaking medical staff of varying backgrounds and experience may be providing service. Some ships use emergency physicians or family practitioners on a rotating basis. Most American medical insurance companies, including Medicare, do not cover these on- board services, and therefore travel insurance is recommended. Use of an air ambulance alone may cost as much as $35,000, de- pending on cabin pressurization requirements and destination. According to the Jones Act, American vessels must show the American flag, be built in America with American steel, and be staffed by an American crew. Services on these vessels are covered by American insurance. However, most cruise companies are Eu- ropean.

The administration of intravenous thrombolytic and adjunctive therapies in patients with evolving acute myocardial infarction has clearly been shown to reduce mortality rates 1, 2 and has become the standard of care. It recanalizes occluded coronary arteries, 3 reduces infarct size, 4 and thereby limits cardiac dysfunction. 5-s The survival advantage is applied unequivocally to patients with infarction who are treated within 4 to 6 hours of symptom onset, have ST elevations, and have no contraindications to thrombolytic therapy. 9 Numerous studies have shown that the rapid initiation of thrombolytic therapy in patients with acute myocardial infarc- tion is of major therapeutic importanceJ °' 11 The effectiveness of the therapy is inversely related to the time of symptom onset. The shorter the interval, the less likely cardiac muscle or life itself will be lost. In the Gusto trial, 12 the 21-day mortality rate was reduced by 18 % in patients treated with streptokinase within 12 hours of

onset of chest pain, by 23 % in patients treated within 3 hours, and by 47 % in patients treated within 1 hour. In the GREAT study, 11 general practitioners provided rapid, high-standard prehospital coronary care. A streamlined protocol can aid in the decision to use thrombolytic therapy and minimize delays. 1316

Most cruise lines do not stock thrombolytics, physicians are not comfortable in its administration or do not have an updated, stan- dardized, written protocol.

We have noted issues concerning patients with medical prob- lems who take cruises on which limited medical services are avail- able. We question the wisdom of the unavailability of thrombolytic therapy on cruise vessels. Administration of thrombolytic therapy after proper screening could be initiated within minutes, resulting in fewer reperfusion arrhythmias and other complications and providing another unique model for the very early time delivery of thrombolytic therapy in acute myocardial infarction.

Michael B. Selig, MD Jonathan Tenzer, DMD

MuhIenberg Hospital Center Bethlehem, PA 18017-7474

REFERENCES 1. Midgette AS, O'Connor GT, Baron JA, Bell J. Effect of intravenous

streptokinase on early mortality in patients with suspected acute my- ocardial infarction. Ann Intern Med 1990;113:961-8.

2. Schroder R, Neuhaus KL, Leizorovicz A, Linderer T, Tebbe U. A pro- spective placebo controlled double blind multicenter trial of intrave- nous streptokinase in acute myocardial infarction (ISAM): long-term mortality and morbidity. J Am Coll Cardiol 1987;9:197-203.

3. TIMI Study Group. Thrombolysis in myocardial infarction trial (TIMI), phase I. N Engl J Med 1985;312:932-6.

4. ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction. Mortality, morbidity and infarct size at 21 days. N Engl J Med 1986;314:1465-71.

5. Gruppo Italiano per Lo Studio della Streptochinasi Nell' Infarcto Mi- ocardico (GISSI). Effectiveness of intravenous thrombolytic therapy in acute myocardial infarction. Lancet 1986;1:397-402.

6. ISIS-II (second international study of infarct survival) collaborative group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither, among 17,187 cases of suspected acute myocardial infarction. Lancet 1988;2:349-60.

7. White HD, Norris RM, Brown MA, Takoyama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987;317:850-5.

8. Van de Werf F, Arnold AER. Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute my- ocardial infarction. BMJ 1988;297:1374-9.

9. Gruppo Italiano Per Lo Studio Della Soprawivenza Nell'Infarcto Mi- ocardico (GISSI-II). A Factorial randomized trial of alteplase vs. strep- tokinase and heparin vs. no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990;336:65-71.

10. European Myocardial Infarction Project Group. Prehospital throm- bolytic therapy with suspected acute myocardial infarction. N Engl J Med 1993;329:383-9.

11. GREAT (Grampian Region Early AntiStreplase Trial) Study Group. Feasibility, safety, and efficacy and domiciliary thrombolysis by general practitioners. BMJ 1992;305:548:53.

12. The Gusto Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:674-82.

13. Sharkey SW, Brunette DD, Ruiz E, Hessron WT, Wysham D, Golden- berg JF, Hodges M. An analysis of time delays preceding thrombolysis in acute myocardial infarction. JAMA 1989;262:3171-4.

14. Weaver WD, Eisenberg MS, Martin JS, Litwin PE, Shaeffer SM, Ho

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MT, Kudenchuk P, Hullstrom AP, Cerqueira MD, Copass MK, Kenedy JW, Cobb LA, Ritchie JL. Myocardial infarction triage and intervention project (MITI) phase I: patient characteristics and feasibility of prehospital initiation of thrombolytic therapy. J Am Coll Cardiol 1990;15:925-31.

15. Selig MB. Acute myocardial infarction: an updated protocol for throm- bolytic therapy. Postgrad Med 1992;92:209-44.

16. Selig MB. Protocol for thrombolytic therapy in acute myocardial infarction: getting the process started. Hudson Monitor 1993;2:29-36.

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NITRATE TOLERANCE

To the Editor: The recent review on nitrate tolerance by Mangione and Glass-

er 1 is an excellent overview of this difficult topic. Having reviewed the relevant history, biochemistry, and mechanisms related to the role of nitrates in therapy and the development of tolerance, they turn to possible ways to prevent tolerance. The only effective way to prevent the development of tolerance is to have a period of sev- eral hours within each 24-hour period during which nitrate levels are allowed to fall to subtherapeutic levels. There are three major ways of achieving this goal. First, a nitrate patch can be worn and removed after 12 hours. Second, a shorter acting, immediate- release nitrate preparation can be administered by eccentric dos- ing (a commonly proposed schedule is 8 AM and 3 PM for mononi- trate tablets) so that most of the treatment is concentrated in the early part of the day and the patient has a nitrate-low period dur- ing the night. Third, the patient is offered a once-daily, long-act- ing nitrate such as mononitrate that is taken in the morning and that after 12 hours gradually falls to subtherapeutic levels. The prescriber chooses one of these and should be aware of their mer- its. At the end of Mangione and Glasser's review, some apparent uncertainties about the slow-release isosorbide mononitrate prep- aration Imdur were made that might detract from its potential value in this context. I should be able to do this without causing offense because I will support my points by referring to another article on which Glasser was a coauthor. 2

According to their Table II, it is unclear whether the once-daily Imdur formulation is effective from day 1. Published data 2 clearly show a significant effect from the first day. The table also gives the time to onset of action of the preparation as 4 hours, at which time the preparation achieves peak plasma concentration; however, therapeutic levels are probably reached within 1 hour, 2 and there is increasing evidence that the preparation is effective by that time. Published data show unequivocally that the drug is effective 3 hours after dosing. 3 Mangione and Glasser state that with isosor- bide mononitrate in ordinary tablets, the duration of action is >_ 12 hours, whereas Imdur is effective for -<12 hours. In the study by Friedman et al.,4 a regimen of isosorbide mononitrate 20 mg twice daily at 7-hour intervals did not produce a statistically significant impact 7 hours after dosing. By comparison, Chrysant et al. 2 showed that 12 hours after Imdur administration the drug was significantly effective. A number of placebo-controlled trials of 3 to 6 week 1 duration have shown that Imdur is effective at a dose of 60 to 120 mg daily. 6, 7 Some studies 2 unequivocally show that Imdur retains its efficacy during at least 42 days of continuous daily administration. 2

My points are clinically relevant because they indicate that one method of long-term nitrate therapy, namely by giving Imdur, al- lows the prescriber to provide effective treatment that starts rel- atively rapidly, lasts for most of the 24 hours, and maintains its efficacy in the long term. The other forms of treatment have their

problems. With the patch technique, it is necessary for the patient to remember to remove the patch and to be aware that the sudden withdrawal of nitrates sometimes produces an exacerbation of the disease. 3 The eccentric regimen is particularly difficult for patients to maintain long term. It is critically important that the spacing of two or three treatments during the day be adhered to; otherwise, the patient may be left unprotected for long periods or, alterna- tively, will risk tolerance development.

M. J. Kendall, MD The University of Birmingham

Department of Medicine Queen Elizabeth Hospital

Edgbaston Birmingham B15 2TH, UK

REFERENCES

1. Mangione NJ, Glasser SP. Phenomenon of nitrate tolerance. AM HEART J 1994;128:137-46.

2. Chrysant SG, Glasser SP, Bittar N, Shahidi E, Danisa K, Ibrahim R, Watts E, Garutti RJ, Ferraresi R, Casareto R. Efficacy and safety of ex- tended release isosorbide mononitrate for stable effort angina. Am J Cardiol 1993;72:1249-56.

3. Kendall MJ. Long-term therapeutic efficacy with once-daily isosorbide- 5-mononitrate (IMDUR). J Clin Pharm Ther 1990;15:169-85.

4. Nyberg G, Carlens P, Lindstrom E, Lundman T, Norlander R, Rehnqvist N, Ulvenstam G, Aberg A, Astrom H. The effects of isisor- bide-5-mononitrate (5-ISMN) Durules on exercise tolerance in patients with exertional angina pectoris. A placebo controlled study. Eur Heart J 1986; 7:835-42.

5. Friedman RG, the ISMN Study Group. Comparative clinical trial of isosorbide mononitrate and isosorbide dinitrate in patients with stable angina pectoris. J Invas Cardiol 1992;4:319-29.

6. Nyberg G. Current status of isosorbide-5-mononitrate therapy. In: Rezakovic DE, Alpert JS, eds. Nitrate therapy and nitrate tolerance. Basel: Karger 1993:358-96.

7. Nyberg G. Current status of isosorbide-5-mononitrate therapy in chronic stable angina pectoris. Am J Ther 1994;1:93-101.

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REPLY

To the Editor: I greatly appreciate Kendall's letter, and I assure him that he

successfully raised several key points. His first concern is the on- set of action of Imdur, and he points to the plasma levels of nitrate achieved after dosing in support of this issue. Indeed, because of this very issue, at my initiation Schering-Plough has recently be- gan a multicenter trial to study the 1-hour clinical efficacy of Im- dur. It was the clinical efficacy that we were referring to in Table II. We used the indicator of --<4 hours in recognition of the pub- lished 3-hour study, but we believe that the real question is not whether Imdur is effective at 3 or 4 hours but whether it is effec- tive at i hour. With respect to the second issue raised by Kendall, duration of action, I especially want to thank him because we did err: instead of the duration of action reading "less than or equal to," it should have read "greater than or equal to."

We do not totally clearly understand Kendall's last point. We did indicate in the table that the efficacy of Imdur was evidenced at day 42 (the end of the study), but we assume that he was con- cerned that the 60 mg dose did not show long-term efficacy. Indeed, this was an extensively discussed issue at a Food and Drug Administration advisory meeting in which it was recognized that in Europe the 60 mg dose had shown efficacy. Parenthetically, in