While there are numerous future trials, studies, and evaluations that could be undertaken, and are elucidated throughout the results section of this report; we believe that the following are areas of particular importance to patient care.

• An individual patient data meta-analysis of major placebo-controlled ACE inhibitor or ARB trials or future trials is needed to provide insight into the benefits and harms in minority groups, including Asians, African Americans and Latinos. We cannot determine the comparative benefits and harms associated with the use of these drugs in these populations based on the data provided to date.
• An individual patient data meta-analysis of major placebo-controlled ACE inhibitor or ARB trials or future trials are needed to provide insight into the benefits and harms in patients with single versus multivessel disease and specifically to determine if left anterior descending artery disease is more important than disease in other vessels in predicting efficacy and harms.
• An individual patient data meta-analysis of major placebo-controlled ACE inhibitor or ARB trials is needed to determine if an association exists with a baseline ejection fraction between 40 percent and 70 percent and the benefits or harms associated with therapy.
• An individual patient data meta-analysis is needed to determine if ACE inhibitors provide greater benefits in patients taking adenosine diphosphate drugs than those taking no antiplatelet therapy to tease out if the interaction noted between antiplatelets and ACE inhibitors is applicable to all antiplatelets or just to aspirin. Determining the impact of antiplatelet therapy on ARB therapy efficacy is also needed.
  • There is moderate strength of evidence from the pooled data analysis of the HOPE and EUROPA trials⁹³ that ACE inhibitors benefit those receiving and not receiving antiplatelet agents as compared to placebo but that those without antiplatelet agents benefit significantly more. However, we cannot be sure that this interaction is between all antiplatelet agents and ACE inhibitors or specifically with aspirin therapy. If it is not attributable to adenosine diphosphate inhibitors then these agents may be substituted for aspirin therapy when ACE inhibitors are used. There is no data on harms in these two subgroups so the balance of benefits to harms cannot be determined in these subgroups. Additionally, no data is available evaluating ARBs in these subgroups. If the benefits derived from ARBs are not impacted by the presence of antiplatelet therapy, this may be a therapeutic alternative to ACE inhibitors.
• An individual patient data meta-analysis is needed to determine if a history of revascularization significantly reduces the benefits associated with ACE inhibitor or ARB therapy and to elucidate the impact on harms associated with these therapies in this population.
  • There is moderate strength of evidence from the pooled data analysis of the HOPE and EUROPA trials⁹³ that ACE inhibitors benefit those with and without a history of revascularization. However, the benefits versus placebo were nonsignificantly better in those without revascularizations. Performing an individual patient data meta-analysis with the inclusion of more trials can discern if there are significantly less benefits in those with revascularization. In addition, harms were not evaluated in these subgroups but this is needed to determine the balance of benefits to harms. There is no subgroup data available evaluating benefits or harms with ARBs in patients with or without revascularization either.
• Future trials are needed to discern if adding ACE inhibitors or ARBs to standard medical therapy in patients with stable ischemic heart disease and preserved left ventricular function is superior or inferior to adding other cardiovascular drugs such as calcium channel blockers.
  • There is moderate strength of evidence from two trials that ACE inhibitor or ARB therapy provides similar benefits as calcium channel blockers. The trials were only of modest size and we cannot evaluate the applicability of these results to subjects of different genders, age, comorbidities, and medications. We were unable to determine if other vasoactive drugs such as thiazide diuretics may also provide a similar level of benefit as ACE inhibitors or ARBs.
• Future trials are needed to determine the benefits and harms associated with adding ACE inhibitors or ARBs to standard medical therapy in patients without proven stable ischemic heart disease but with ischemic heart disease risk equivalents.
  • The applicability of these results to subjects of different genders, age, comorbidities, and medications are needed.
• Future studies are needed to determine if the dosing intensity of ACE inhibitor or ARB therapy is related to the extent of efficacy and harms that patients receive.
• Future trials are needed to determine the impact of genetic polymorphisms within the ACE gene or the angiotensin II type 1 receptor and the benefits or harms associated with ACE inhibitors or ARBs in this population.
• Of note, a review of trials registered at www.clinicaltrials.gov [Accessed January 8, 2009] revealed no ongoing trials that would have matched our inclusion criteria or answered any of the remaining clinical questions proposed in this section.