ABSTRACT
In 1999, the Center for Biologics Evaluation and Research (CBER) of the U�S� Food and Drug Administration (FDA) determined that for phase 3 studies, “a result where the 95% one-sided confidence interval of the relative risk of mortality of the new thrombolytic [versus an accelerated tissue plasminogen activator regimen (tPA90)] that excludes a value of 1�143 provides evidence that the new thrombolytic agent has retained sufficient efficacy to be supportive of a marketing application” (FDA/CBER Memorandum 1999)� In other words, the null hypothesis of interest is given by Equation 3�2 in Section 3�4 of Chapter 3 (adapted to relative risk), where r = 1�143; that is,
H : T/S r 1�1430 ≥ =
versus
=H : T/S < r 1�1431
or
H : (new thrombolytic)/tPA90 r 1�1430 ≥ =
versus
H : (new thrombolytic)/tPA90 r 1�1431 < =
The main purpose of this chapter is to revisit the determination of 1�143, as opposed to presenting up-to-date information regarding the thrombolytic therapies for acute myocardial infarction�
11.2.1 Thrombolytic and Fibrinolytic Therapies for Acute Myocardial Infarction
This subsection introduces the medical term of heart attack and a brief history of its treatment�
Myocardial infarction (MI) or acute myocardial infarction (AMI) is the medical term for an event commonly known as a heart attack� It happens when blood stops flowing properly to part of the heart and the heart muscle is injured due to not receiving enough oxygen� Usually, this is because one of the coronary arteries that supplies blood to the heart develops a blockage due to an unstable buildup of white blood cells, cholesterol, and fat� The event is called “acute” if it is sudden and serious (Wikipedia Contributors 2014a)�
”Thrombolytic therapy is the use of drugs to break up or dissolve blood clots, which are the main cause of both heart attacks and stroke� The most commonly used drug for thrombolytic therapy is tissue plasminogen activator (tPA)�” (Medline Plus 2014)� On the other hand, “fibrinolytic therapy involves the use of drugs that dissolve clots by breaking down fibrin-a protein that connects with another sticky element of the blood known as platelets to form clots” (Canadian Medical Association Journal 2001)� Briefly, “thrombolytics break down clots, and fibrinolytics specifically break down the fibrin in the clot” (Answers 2014)�
The thrombolytic drugs, with brand names given in parentheses, include
1� Tissue plasminogen activators (tPA) a� Alteplase (Activase) b� Reteplase (Retavase) c� Tenecteplase (TNKase)
2� Anistreplase (Eminase) 3� Streptokinase (Kabikinase, Streptase) 4� Urokinase (Abbokinase)
“These drugs are often administered in combination with anticoagulant drugs, such as intravenous heparin or low-molecular-weight heparin, for synergistic antithrombotic effects and secondary prevention” (Wikipedia Contributors 2014b)�
During the 1980s and early 1990s, four large, randomized, placebocontrolled trials showed that intravenous thrombolytic therapy with streptokinase improved survival in AMI subjects (GISSI-1 1986; ISAM 1986; ISIS-2 1988; and EMERAS 1993) (see Sections 11�2�2 and 11�3�3)� However, the antigenicity and minimal fibrin specificity of streptokinase
were undesirable� These undesirable properties spurred interest in finding other potential thrombolytic agents� In February 1984, a 57-year-old woman with an acute occlusion of her left anterior descending artery was the first patient who was successfully treated with recombinant tPA at the Johns Hopkins Hospital (Maroo and Topol 2004)� In 1993, the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) study showed that tPA resulted in a 15% reduction in mortality, as compared to streptokinase (GUSTO Investigators 1993) (see Section 11�2�3)�
In 1992, the Cardio-Renal Advisory Committee recommended that a new thrombolytic must retain at least 50% of the benefit of the control thrombolytic� In a meta-analysis paper published by the Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group (1994) (see Section 11�2�2), the benefit of streptokinase over placebo was placed at 2�6% in overall mortality rates� Based on this information, reteplase was compared with streptokinase in an equivalence trial to show that it retains at least 50% of the mortality benefit (i�e�, a margin of 1�3% was used)� Activase and reteplase had been approved by the FDA based on their comparisons with streptokinase in equivalence studies (Gupta et al� 1999)�
11.2.2 Meta-Analysis Conducted by the Fibrinolytic Therapy Trialists’ Collaborative Group
The Fibrinolytic Therapy Trialists’ Collaborative Group (FTT Collaborative Group, 1994) conducted a meta-analysis of the effects of treatment on mortality and on major morbidity in various patient categories in those trials designed to randomize more than 1,000 patients with suspected AMI between fibrinolytic therapy and control� There were nine such trials: GISSI-1, ISAM, AIMS, ISIS-2, ASSETS, USIM, ISIS-3 (“uncertain indication” group), EMERAS, and LATE (see Table 11�1), and the number of patients included in these studies were 11,802, 1,741, 1,254, 17,187, 5,012, 2,201, 9,158, 4,534, and 5,711, respectively�
In ISIS-3 (1992), patients for whom their physicians thought there was a “clear” indication for fibrinolytic therapy (n = 36,381) were randomized equally between SK, tPA, and APSAC, whereas those for whom the indication was considered “uncertain” (n = 9,475) were randomized equally between fibrinolytic therapy (SK, tPA, or APSAC) and open control (i�e�, no placebo)� On the other hand, the FTT Collaborative Group (1994) reported only 9,158 patients in the “uncertain” subgroup�
ISIS-3 (1992) reported the results among all 41,299 patients, whether in the “clear” or “uncertain” indication category, who were to receive fibrinolytic therapy� The agent was streptokinase (SK) in four; anistreplase (APSAC) in one; tissue plasminogen activator (tPA; alteplase or duteplase) in two; urokinase (UK) in one; and a random choice of SK, tPA, or APSAC in one� Six trials were placebo controlled, while three trials randomized patients
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